Inhibitors of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and methods of use thereof

ABSTRACT

Compounds and methods for their preparation and use as therapeutic or prophylactic agents, for example for treatment of cancer, bacterial or viral diseases by targeting Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 (ENPP1).

FIELD OF THE INVENTION

The present invention generally relates to inhibitors of EctonucleotidePyrophophatase/Phosphodiesterase (ENPP1). The invention is directed topharmaceutical compositions containing the Formula 1 or Formula 2compounds and methods of using the compounds or compositions to treatvarious types of human cancers where the ENPP1 is overexpressed,cardiovascular, diabetes, obesity, NASH, glaucoma, antiviral,antibacterial and anti-fibrotic therapeutics. The invention is alsodirected to methods of making the compounds and its pharmaceuticalssalts.

BACKGROUND OF THE INVENTION

Ectonucleotide Pyrophophatase/Phosphodiesterase (ENPP) family membersinclude seven isoforms, ENPP1-7, which are type II transmembraneglycoproteins or ectoenzymes. Mass spectrometry and proteomics analysisfrom more than 370 protein targets led to the identification of anextracellular protein ENPP1 as one of the top hits which exhibited highhydrolytic activity. ATP is an identified substrate of ENPP1, which ishydrolyzed to AMP and PPi. CD73 converts AMP to adenosine and inorganicphosphate (Pi). The kinetic experimental data indicates that the ENPP1is capable of hydrolyzing ATP. These ectonucleotide enzymes are involvedin the hydrolysis of pyrophosphate (PPi) and phosphodiester bonds inextracellular nucleotides; such as triphosphates, oligonucleotides andthat generates nucleoside 5′-monophosphates. One of the key isoforms,ENPP1 (Plasma cell membrane glycoprotein-1, PC-1), is involved in anumber of physiological processes, such as development, formation andtrafficking, as well as in pathophysiological conditions. Aberrant ENPP1expression has been detected in breast cancers relative to normalmammary epithelium, an evidence of its potential in the development ofbone metastasis (occurs in approximately 80% cases), Hodgkin's lymphoma,hepatocellular carcinoma, follicular lymphoma, glioblastoma and in othermalignant tumor tissues.

Recent reports suggest that the cyclic dinucleotides (CDNs), a substratefor ENPP1, stimulate innate immunity via STING-dependent activation ofinterferon genes. ENPP1 inhibition of STING pathway activation iscritical for tumor control, similar to that of checkpoint inhibitorssuch as anti PD-1 or PD-L1 which are promising immunotherapeutics forvarious cancers. In addition, mutations in ENPP1 were associated withseveral disorders including infantile arterial calcification(generalized arterial calcification of infancy or GACI), ossification ofthe posterior longitudinal ligament of the spine and insulin signalingand resistance. ENPP1 expression is high in bone and cartilage and isimplicated in lung and kidney fibrosis. A correlation was also foundbetween expression of ENPP1 and the grade of astrocytic tumor. Anotherstudy reported that ENPP1 was required to maintain the undifferentiatedand proliferative state of glioblastoma stem-like cells. Therefore,ENPP1 is an attractive druggable target for the development of novelanticancer, cardiovascular, diabetes, obesity, NASH, glaucoma, andanti-fibrotic therapeutics.

Importance of ENPP1 activity was further investigated from both directbinding assay and in vitro cellular efficacy on MDA-MB231 cells. ThesiRNA-based knock down of ENPP1 significantly reduced its catalyticactivity both in cell specific and in vivo experiments. Theseexperiments demonstrated that the ENPP1 activity was abolished ontreatment with siRNA. This further supports the validity of this targetin certain diseases. It has been shown recently that thebisphosphothionate analog of endogenous cGAMP is resistant to hydrolysisby ENPP1 phosphodiesterase, and particularly the cyclic dinucleotides(CDNs) are more potent at inducing IFN-β secretion in human THP1 cellsby a mechanism of inhibiting the ENPP1 activity and simultaneous STINGactivation responses.

There is ample evidence that ENPP1 expression is prominent in humanprimary breast tumors relative to normal mammary epithelium, withhighest levels observed in breast-bone metastasis. These data not onlysupport a potential role for ENPP1 in breast-bone metastasis, but alsosupport as a potential prognostic marker for breast cancer. Morerecently, ENPP1 was shown to be upregulated in lung cancer. Knockdown ofENPP1 in lung cancer cell lines HCC827 and A549 resulted in suppressedcolonogenic formation, anchorage-independent growth in vitro, andtumorigenicity in vivo. These results from target validation experimentsclearly support the pharmacological role of ENPP1 for the development ofnovel immunotherapeutics for cancers.

Furthermore, ENPP1 activity has also been implicated in diseases causedby bacteria and/or viruses, and therefore modulators of ENPP1 can beused to treat bacterial and/or viral diseases and conditions.

SUMMARY OF THE INVENTION

The invention, in one aspect, relates to compounds of Formula I orFormula II as follows:

whereinX is N or CR₁₁;Y is selected from the group consisting of —CR₄R₅—, —NR₆—,—N(CH₂)_(m)O—, —O—, —S—, —S(O)—, —S(O)₂, aryl, and heteroaryl; wherein mis 2 or 3;L is selected from the group consisting of an C₁-C₅ alkyl, and C₁-C₅alkenyl;each R₁, R₂ and R₃ are independently selected from the group consistingof hydrogen, halogen, CN, OR^(a), —C(═O)NR^(b)R^(c), —NR^(b)R^(c),—C(═O)R^(d), aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.each R^(a) is independently selected from the group consisting ofhydrogen, lower alkyl, —(CH₂)_(n)—C(═O)NR^(b)R^(c), aralkyl, aryl,heteroaryl, heterocycloalkyl, and cycloalkyl;wherein n is an integer between 1 and 3;each R^(b) and R^(c) is independently selected from the group consistingof hydrogen, a lower alkyl, and lower aryl, heterocycloalkyl, orcycloalkyl;each R^(d) is independently selected from the group consisting of—OR^(e) and lower alkyl;each R^(e) is independently selected from the group consisting ofhydrogen, a lower alkyl, and a lower aryl;R₁₁ is independently selected from the group consisting of hydrogen,halogen, COOEt, COOH, and CN;R₄, R₅ and R₆ are independently selected from the group consisting ofhydrogen and lower alkyl;or an isomer, hydrate, solvate, polymorph, tautomer or apharmaceutically acceptable salt thereof.

A compound of Formula II is as follows:

whereinX is N or CR₁₁;Z is C or N;W is selected from the group consisting of an C₁-C₅ alkyl,—C(═O)—(CH₂)_(n)—, —(C₁-C₅ alkyl)-N—; NH, and a direct bond as follows:

each R₁; R₂ and R₃ are independently selected from the group consistingof hydrogen, halogen, CN, OR^(a), —C(═O)NR^(b)R^(c), —NR^(b)R^(c),—C(═O)R^(d), aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.each R^(a) is independently selected from the group consisting ofhydrogen, lower alkyl, and —(CH₂)_(n)—C(═O)NR^(b)R^(c), aralkyl, aryl,heteroaryl, heterocycloalkyl, cycloalkyl;wherein n is an integer between 1 and 3;each R^(b) and R^(c) is independently selected from the group consistingof hydrogen, a lower alkyl, and lower aryl, heterocycloalkyl, orcycloalkyl;each R^(d) is independently selected from the group consisting of—OR^(e) and lower alkyl;each R^(e) is independently selected from the group consisting ofhydrogen, a lower alkyl, and a lower aryl;R₁₁ is independently selected from the group consisting of hydrogen,halogen, COOEt, COOH, and CN;R₇, R₈ and R₉ are independently selected from the group consisting of H,halogen and lower alkyl; and R₈ and R₉ can also form a bridge across the7-membered ring with 1 or 2 atoms, as follows:

R₁₀ is independently selected from the group consisting of hydrogen andCF₃;or an isomer, hydrate, solvate, polymorph, tautomer or apharmaceutically acceptable salt thereof.

The invention encompasses any compounds or structures that include anycombinations of the substituents as defined above.

In one preferred embodiment, Y in Formula I is pyridinyl.

In one preferred embodiment, X in Formula I or Formula II is C—CN.

In one preferred embodiment, Y in Formula I is NR₆.

In one preferred embodiment, in compounds of Formula I and Formula II,R₁, R₂ and R₃ are selected from the group consisting of CH₃O and H.

In one preferred embodiment, in compounds of Formula II, Z is N.

In one preferred embodiment, in compounds of Formula II, W is selectedfrom the group consisting of -4,5-imidazole, 2-Oxazole, 3-pyrrole;pyrazole, and thiazole.

In one preferred embodiment, in compounds of Formula II, X is N.

In one preferred embodiment, in compounds of Formula II, X is C—CN.

In one preferred embodiment, in compounds of Formula II, R₇, R₈ and R₉are independently selected from the group consisting of H and halogen.

In one preferred embodiment, in compounds of Formula II, R₇ is ahalogen, and more preferably F.

In one preferred embodiment,

the compound is of Formula I;

X is N;

Y is selected from the group consisting of pyridinyl, C₁-C₅ alkyl, O, N,and S;

L is an optionally substituted C₁-C₅ alkyl; and

R₁ and R₂ are both CH₃O.

In another preferred embodiment,

the compound is of Formula II;

X is N;

Z is N;

W is selected from the group consisting of an optionally substitutedC₁-C₅ alkyl, —C(═O)—(CH₂)—, —(an optionally substituted C₁-C₅ alkyl)-N;and a direct bond; and

R₁ and R₂ are both CH₃O.

Examples of the provided compounds include:

The invention also includes hydrates, solvates, polymorphs, isomers,tautomers of the compounds, pharmaceutically acceptable salts of thecompounds and pharmaceutically acceptable salts of the tautomers.

The invention also provides pharmaceutical formulations, medicamentsincluding the compounds, methods of preparing pharmaceuticalsformulations, medicaments, compounds, and methods of treating patientswith the provided pharmaceutical formulations and compounds.

The compounds of the invention were identified by structure-based,computational docking and binding free energies.

Also disclosed are pharmaceutical compositions comprising atherapeutically effective amount of a disclosed compound and apharmaceutically acceptable carrier.

Also disclosed are synthetic methods for making the disclosed compounds.In a further aspect, disclosed are the products of the disclosedsynthetic methods.

Also disclosed are methods for the treatment of a disorder associatedwith an ENPP1 activity dysfunction in a mammal comprising the step ofadministering to the mammal a therapeutically effective amount of adisclosed compound, or a pharmaceutically acceptable salt, tautomer,isomer, hydrate, solvate, or polymorph thereof.

Also disclosed are methods for inhibition of ENPP1 activity in a mammalcomprising the step of administering to the mammal a therapeuticallyeffective amount of least one disclosed compound, or a pharmaceuticallyacceptable salt, tautomer, isomer, hydrate, solvate, or polymorphthereof.

Also disclosed are methods for inhibiting ENPP1 activity in at least onecell, comprising the step of contacting the at least one cell with aneffective amount of least one disclosed compound, or a pharmaceuticallyacceptable salt, tautomer, isomer, hydrate, solvate, or polymorphthereof.

Also disclosed are methods for treating a disorder associated with anENPP1 activity dysfunction in a mammal through eliciting animmunotherapeutic response in the mammal, comprising administering tothe mammal a therapeutically effective amount of a disclosed compound,or a pharmaceutically acceptable salt, tautomer, isomer, hydrate,solvate, or polymorph thereof, wherein this compound causes animmunotherapeutic response beneficial in the treatment of the disorderassociated with an ENPP1 activity. Such disorder can be, but is notlimited to, any type of cancer or any disease caused by bacteria and/orviruses wherein ENPP1 activity has been implicated. Diseases andconditions treatable by the compounds of the present invention include,but are not limited to, cancers, cardiovascular diseases, diabetes,obesity, NASH, glaucoma, fibrotic antiviral, antibacterial andanti-fibrotic therapeutics.

Also disclosed are pharmaceutical compositions comprising apharmaceutically acceptable carrier and an effective amount of adisclosed compound, or a pharmaceutically acceptable salt, tautomer,isomer, hydrate, solvate, or polymorph thereof.

Also disclosed are kits comprising at least one disclosed compound, or apharmaceutically acceptable salt, tautomer, isomer, hydrate, solvate, orpolymorph thereof.

Also disclosed are methods for manufacturing a medicament comprising,combining at least one disclosed compound or at least one disclosedproduct with a pharmaceutically acceptable carrier or diluent. In afurther aspect, the invention relates to the use of a disclosed compoundin the manufacture of a medicament for the treatment of a disorderassociated with an ENPP1 activity dysfunction. In a further aspect, theinvention relates to the uses of disclosed compounds in the manufactureof a medicament for the treatment of a disorder of uncontrolled cellularproliferation.

Also disclosed are uses of a disclosed compound or a disclosed productin the manufacture of a medicament for the treatment of a disorderassociated with an ENPP1 dysfunction in a mammal.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a chart of ENPP inhibition of transfected HEK293T cellslysates by compounds of the invention.

FIG. 2 shows results of Immune Infiltration Assay in HP AC cells.

FIG. 3 shows a PK profile of Compound 015-HCl in rat.

FIG. 4A shows an in vivo inhibition of tumor with Compound 015-HCl.

FIG. 4B shows an in vivo inhibition of tumor with Compound 015-HClcombined with radiation treatment.

DETAILED DESCRIPTION OF THE INVENTION A. Definitions

As used herein, nomenclature for compounds, including organic compounds,can be given using common names, IUPAC, IUBMB, or CAS recommendationsfor nomenclature. When one or more stereochemical features are present,Cahn-Ingold-Prelog rules for stereochemistry can be employed todesignate stereochemical priority, E/Z specification, and the like. Oneof skill in the art can readily ascertain the structure of a compound ifgiven a name, either by systemic reduction of the compound structureusing naming conventions, or by commercially available software, such asChemDraw™ (Cambridgesoft Corporation, U.S.A.).

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, a further aspect includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms a further aspect. It willbe further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint. It is also understood that there are a number ofvalues disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, the term “ENPP1” refers to EctonucleotidePyrophophatase/Phosphodiesterase.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or can not occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the term “subject” can be a vertebrate, such as amammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject ofthe herein disclosed methods can be a human, non-human primate, horse,pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The termdoes not denote a particular age or sex. Thus, adult and newbornsubjects, as well as fetuses, whether male or female, are intended to becovered. In one aspect, the subject is a mammal. A patient refers to asubject afflicted with a disease or disorder. The term “patient”includes human and veterinary subjects. In some aspects of the disclosedmethods, the subject has been diagnosed with a need for treatment of adisorder of uncontrolled cellular proliferation associated with an ENPP1dysfunction prior to the administering step. In some aspects of thedisclosed method, the subject has been diagnosed with a need forinhibition of ENPP1 prior to the administering step.

As used herein, the term “treatment” refers to the medical management ofa patient with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder. In various aspects, the term covers anytreatment of a subject, including a mammal (e.g., a human), andincludes: (i) preventing the disease from occurring in a subject thatcan be predisposed to the disease but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, i.e., arresting its development;or (iii) relieving the disease, i.e., causing regression of the disease.In one aspect, the subject is a mammal such as a primate, and, in afurther aspect, the subject is a human. The term “subject” also includesdomesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle,horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse,rabbit, rat, guinea pig, fruit fly, zebra fish etc.).

As used herein, the term “prevent” or “preventing” refers to precluding,averting, obviating, forestalling, stopping, or hindering something fromhappening, especially by advance action. It is understood that wherereduce, inhibit or prevent are used herein, unless specificallyindicated otherwise, the use of the other two words is also expresslydisclosed.

As used herein, the term “diagnosed” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have a condition that can be diagnosed or treated by thecompounds, compositions, or methods disclosed herein. For example,“diagnosed with a disorder of uncontrolled cellular proliferation” meanshaving been subjected to a physical examination by a person of skill,for example, a physician, and found to have a condition that can bediagnosed or treated by a compound or composition that can inhibitENPP1. As a further example, “diagnosed with a need for inhibition ofENPP1” refers to having been subjected to a physical examination by aperson of skill, for example, a physician, and found to have a conditioncharacterized by an ENPP1 dysfunction. Such a diagnosis can be inreference to a disorder, such as a disorder of uncontrolled cellularproliferation, cancer and the like, as discussed herein. For example,“diagnosed with a need for treatment of one or more disorders ofuncontrolled cellular proliferation associated with an ENPP1dysfunction” means having been subjected to a physical examination by aperson of skill, for example, a physician, and found to have one or moredisorders of uncontrolled cellular proliferation associated with anENPP1 dysfunction.

As used herein, the phrase “identified to be in need of treatment for adisorder,” or the like, refers to selection of a subject based upon needfor treatment of the disorder. For example, a subject can be identifiedas having a need for treatment of a disorder (e.g., a disorder relatedto a dysfunction of ENPP1) based upon an earlier diagnosis by a personof skill and thereafter subjected to treatment for the disorder. It iscontemplated that the identification can, in one aspect, be performed bya person different from the person making the diagnosis. It is alsocontemplated, in a further aspect, that the administration can beperformed by one who subsequently performed the administration.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, sublingual administration, buccal administration,intraurethral administration, and parenteral administration, includinginjectable such as intravenous administration, intra-arterialadministration, intramuscular administration, and subcutaneousadministration. Administration can be continuous or intermittent. Invarious aspects, a preparation can be administered therapeutically; thatis, administered to treat an existing disease or condition. In furthervarious aspects, a preparation can be administered prophylactically;that is, administered for prevention of a disease or condition.

The term “contacting” as used herein refers to bringing a disclosedcompound and a cell, target receptor, or other biological entitytogether in such a manner that the compound can affect the activity ofthe target (e.g., receptor, cell, etc.), either directly; i.e., byinteracting with the target itself, or indirectly; i.e., by interactingwith another molecule, co-factor, factor, or protein on which theactivity of the target is dependent.

As used herein, the terms “effective amount” and “amount effective”refer to an amount that is sufficient to achieve the desired result orto have an effect on an undesired condition. For example, a“therapeutically effective amount” refers to an amount that issufficient to achieve the desired therapeutic result or to have aneffect on undesired symptoms, but is generally insufficient to causeadverse side affects. The specific therapeutically effective dose levelfor any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the specific composition employed; the age, body weight, general health,sex, and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of a compound at levels lower than those required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved. If desired, the effective dailydose can be divided into multiple doses for purposes of administration.Consequently, single dose compositions can contain such amounts orsubmultiples thereof to make up the daily dose. The dosage can beadjusted by the individual physician in the event of anycontraindications. Dosage can vary, and can be administered in one ormore dose administrations daily, for one or several days. Guidance canbe found in the literature for appropriate dosages for given classes ofpharmaceutical products. In further various aspects, a preparation canbe administered in a “prophylactically effective amount”; that is, anamount effective for prevention of a disease or condition.

As used herein, “EC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50% agonismor activation of a biological process, or component of a process,including a protein, subunit, organelle, ribonucleoprotein, etc. In oneaspect, an EC₅₀ can refer to the concentration of a substance that isrequired for 50% agonism or activation in vivo, as further definedelsewhere herein. In a further aspect, EC₅₀ refers to the concentrationof agonist or activator that provokes a response halfway between thebaseline and maximum response.

As used herein, “IC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50%inhibition of a biological process, or component of a process, includinga protein, subunit, organelle, ribonucleoprotein, etc. For example, anIC₅₀ can refer to the concentration of a substance that is required for50% inhibition in vivo or the inhibition is measured in vitro, asfurther defined elsewhere herein. Alternatively, IC₅₀ refers to the halfmaximal (50%) inhibitory concentration (IC) of a substance. Theinhibition can be measured in a cell-line such as AN3 CA, BT-20, BT-549,HCT 116, HER218, MCF7, MDA-MB-231, MDA-MB-235, MDA-MB-435S, MDA-MB-468,PANC-1, PC-3, SK-N-MC, T-47D, and U-87 MG.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable, i.e., without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner.

The term “stable,” as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and, in certain aspects, their recovery,purification, and use for one or more of the purposes disclosed herein.

As used herein, the term “derivative” refers to a compound having astructure derived from the structure of a parent compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, amides, salts ofesters or amides, and N-oxides of a parent compound.

As used herein, the term “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions can also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

A residue of a chemical species, as used in the specification andconcluding claims, refers to the moiety that is the resulting product ofthe chemical species in a particular reaction scheme or subsequentformulation or chemical product, regardless of whether the moiety isactually obtained from the chemical species. Thus, an ethylene glycolresidue in a polyester refers to one or more —OCH₂CH₂O— units in thepolyester, regardless of whether ethylene glycol was used to prepare thepolyester. Similarly, a sebacic acid residue in a polyester refers toone or more —CO(CH₂)₈CO— moieties in the polyester, regardless ofwhether the residue is obtained by reacting sebacic acid or an esterthereof to obtain the polyester.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. It is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

In defining various terms, R₁; R₂, R₃, etc and R^(a), R^(b), R^(c),R^(d), etc are used herein as generic symbols to represent variousspecific substituents. These symbols can be any substituent, not limitedto those disclosed herein, and when they are defined to be certainsubstituents in one instance, they can, in another instance, be definedas some other substituents.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, 5-butyl, t-butyl, n-pentyl,isopentyl, 5-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl,dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Thealkyl group can be cyclic or acyclic. The alkyl group can be branched orunbranched. The alkyl group can also be substituted or unsubstituted.For example, the alkyl group can be substituted with one or more groupsincluding, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether,halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.A “lower alkyl” group is an alkyl group containing from one to six(e.g., from one to four) carbon atoms.

For example, a “C₁-C₃ alkyl” group can be selected from methyl, ethyl,n-propyl, i-propyl, and cyclopropyl, or from a subset thereof. Incertain aspects, the “C₁-C₃ alkyl” group can be optionally furthersubstituted. As a further example, a “C₁-C₄ alkyl” group can be selectedfrom methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl,s-butyl, t-butyl, and cyclobutyl, or from a subset thereof. In certainaspects, the “C₁-C₄ alkyl” group can be optionally further substituted.As a further example, a “C₁-C₆ alkyl” group can be selected from methyl,ethyl, 72-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl,t-butyl, cyclobutyl, n-pentyl, i-pentyl, 5-pentyl, t-pentyl, neopentyl,cyclopentyl, n-hexyl, i-hexyl, 3-methylpentane, 2,3-dimethylbutane,neohexane, and cyclohexane, or from a subset thereof. In certainaspects, the “C₁-C₆ alkyl” group can be optionally further substituted.As a further example, a “C₁-C₈ alkyl” group can be selected from methyl,ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl,t-butyl, cyclobutyl, n-pentyl, i-pentyl, 5-pentyl, t-pentyl, neopentyl,cyclopentyl, n-hexyl, i-hexyl, 3-methylpentane, 2,3-dimethylbutane,neohexane, cyclohexane, heptane, cycloheptane, octane, and cyclooctane,or from a subset thereof. In certain aspects, the “C₁-C₈ alkyl” groupcan be optionally further substituted. As a further example, a “C₁-C₁₂alkyl” group can be selected from methyl, ethyl, n-propyl, i-propyl,cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclobutyl, n-pentyl,i-pentyl, 5-pentyl, t-pentyl, neopentyl, cyclopentyl, n-hexyl, i-hexyl,3-methylpentane, 2,3-dimethylbutane, neohexane, cyclohexane, heptane,cycloheptane, octane, cyclooctane, nonane, cyclononane, decane,cyclodecane, undecane, cycloundecane, dodecane, and cyclododecane, orfrom a subset thereof. In certain aspects, the “C₁-C₁₂ alkyl” group canbe optionally further substituted.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” or “haloalkyl” specifically refers to analkyl group that is substituted with one or more halide, e.g., fluorine,chlorine, bromine, or iodine. The term “alkoxyalkyl” specifically refersto an alkyl group that is substituted with one or more alkoxy groups, asdescribed below. The term “alkylamino” specifically refers to an alkylgroup that is substituted with one or more amino groups, as describedbelow, and the like. When “alkyl” is used in one instance and a specificterm such as “alkylalcohol” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“alkylalcohol” and the like.

This practice is also used for other groups described herein. That is,while a term such as “cycloalkyl” refers to both unsubstituted andsubstituted cycloalkyl moieties, the substituted moieties can, inaddition, be specifically identified herein; for example, a particularsubstituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl.” Similarly, a substituted alkoxy can be specificallyreferred to as, e.g., a “halogenated alkoxy,” a particular substitutedalkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, thepractice of using a general term, such as “cycloalkyl,” and a specificterm, such as “alkylcycloalkyl,” is not meant to imply that the generalterm does not also include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is atype of cycloalkyl group as defined above, and is included within themeaning of the term “cycloalkyl,” where at least one of the carbon atomsof the ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group andheterocycloalkyl group can be substituted or unsubstituted. Thecycloalkyl group and heterocycloalkyl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, nitrile,sulfonamide, or thiol as described herein.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, phenoxybenzene, and the like. The term “aryl” alsoincludes “heteroaryl,” which is defined as a group that contains anaromatic group that has at least one heteroatom incorporated within thering of the aromatic group. Examples of heteroatoms include, but are notlimited to, nitrogen, oxygen, sulfur, and phosphorus. Likewise, the term“non-heteroaryl,” which is also included in the term “aryl,” defines agroup that contains an aromatic group that does not contain aheteroatom. The aryl group can be substituted or unsubstituted. The arylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, nitrile,sulfonamide, or thiol as described herein. The term “biaryl” is aspecific type of aryl group and is included in the definition of “aryl.”Biaryl refers to two aryl groups that are bound together via a fusedring structure, as in naphthalene, or are attached via one or morecarbon-carbon bonds, as in biphenyl.

The terms “halogen,” “halide,” and “halo,” as used herein, refer to thehalogens fluorine, chlorine, bromine, and iodine. It is alsocontemplated that, in various aspects, halogen can be selected fromfluoro, chloro, bromo, and iodo. For example, halogen can be selectedfrom fluoro, chloro, and bromo. As a further example, halogen can beselected from fluoro and chloro. As a further example, halogen can beselected from chloro and bromo. As a further example, halogen can beselected from bromo and iodo. As a further example, halogen can beselected from chloro, bromo, and iodo. In one aspect, halogen can befluoro. In a further aspect, halogen can be chloro. In a still furtheraspect, halogen is bromo. In a yet further aspect, halogen is iodo.

It is also contemplated that, in certain aspects, pseudohalogens (e.g.triflate, mesylate, tosylate, brosylate, etc.) can be used in place ofhalogens. For example, in certain aspects, halogen can be replaced bypseudohalogen. As a further example, pseudohalogen can be selected fromtriflate, mesylate, tosylate, and brosylate. In one aspect,pseudohalogen is triflate. In a further aspect, pseudohalogen ismesylate. In a further aspect, pseudohalogen is tosylate. In a furtheraspect, pseudohalogen is brosylate.

The term “heterocycle,” as used herein refers to single and multi-cyclicaromatic or non-aromatic ring systems in which at least one of the ringmembers is other than carbon. Heterocycle includes azetidine, dioxane,furan, imidazole, isothiazole, isoxazole, morpholine, oxazole, oxazole,including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole,piperazine, piperidine, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, pyrrolidine, tetrahydrofuran, tetrahydropyran,tetrazine, including 1,2,4,5-tetrazine, tetrazole, including1,2,3,4-tetrazole and 1,2,4,5-tetrazole, thiadiazole, including,1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, thiazole,thiophene, triazine, including 1,3,5-triazine and 1,2,4-triazine,triazole, including, 1,2,3-triazole, 1,3,4-triazole, and the like.

The term “hydroxyl” as used herein is represented by the formula —OH.

“R¹,” “R²,” “R³,” “R^(n),” where n is an integer, as used herein can,independently, possess one or more of the groups listed above. Forexample, if R¹ is a straight chain alkyl group, one of the hydrogenatoms of the alkyl group can optionally be substituted with a hydroxylgroup, an alkoxy group, an alkyl group, a halide, and the like.Depending upon the groups that are selected, a first group can beincorporated within second group or, alternatively, the first group canbe pendant (i.e., attached) to the second group. For example, with thephrase “an alkyl group comprising an amino group,” the amino group canbe incorporated within the backbone of the alkyl group. Alternatively,the amino group can be attached to the backbone of the alkyl group. Thenature of the group(s) that is (are) selected will determine if thefirst group is embedded or attached to the second group.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, unless explicitly stated otherwise, achemical group may be substituted, regardless whether it is explicitlystated that it is “optionally substituted”. In general, the term“substituted,” whether preceded by the term “optionally” or not, meansthat one or more hydrogens of the designated moiety are replaced with asuitable substituent. Unless otherwise indicated, an “optionallysubstituted” group may have a suitable substituent at each substitutableposition of the group, and when more than one position in any givenstructure may be substituted with more than one substituent selectedfrom a specified group, the substituent may be either the same ordifferent at every position. Combinations of substituents envisioned bythis invention are preferably those that result in the formation ofstable or chemically feasible compounds. In is also contemplated that,in certain aspects, unless expressly indicated to the contrary,individual substituents can be further optionally substituted (i.e.,further substituted or unsubstituted).

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the inventionincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present invention includes all such possible diastereomersas well as their racemic mixtures, their substantially pure resolvedenantiomers, all possible geometric isomers, and pharmaceuticallyacceptable salts thereof. Mixtures of stereoisomers, as well as isolatedspecific stereoisomers, are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

All the enantiomers were separated by SFC column and the stereochemistryis tentative.

Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and l or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or l meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomercan also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric mixture. A 50:50 mixture of enantiomersis referred to as a racemic mixture.

Many of the compounds described herein can have one or more chiralcenters and therefore can exist in different enantiomeric forms. Ifdesired, a chiral carbon can be designated with an asterisk (*). Whenbonds to the chiral carbon are depicted as straight lines in thedisclosed formulas, it is understood that both the (R) and (S)configurations of the chiral carbon, and hence both enantiomers andmixtures thereof, are embraced within the formula. As is used in theart, when it is desired to specify the absolute configuration about achiral carbon, one of the bonds to the chiral carbon can be depicted asa wedge (bonds to atoms above the plane) and the other can be depictedas a series or wedge of short parallel lines is (bonds to atoms belowthe plane). The Cahn-Inglod-Prelog system can be used to assign the (R)or (S) configuration to a chiral carbon.

Such as

Compounds described herein comprise atoms in both their natural isotopicabundance and in non-natural abundance. The disclosed compounds can beisotopically-labelled or isotopically-substituted compounds identical tothose described, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number typically found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F and ³⁶Cl,respectively. Compounds further comprise prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of the present invention and prodrugsthereof can generally be prepared by carrying out the procedures below,by substituting a readily available isotopically labelled reagent for anon-isotopically labelled reagent.

The compounds described in the invention can be present as a solvate. Insome cases, the solvent used to prepare the solvate is an aqueoussolution, and the solvate is then often referred to as a hydrate. Thecompounds can be present as a hydrate, which can be obtained, forexample, by crystallization from a solvent or from aqueous solution. Inthis connection, one, two, three or any arbitrary number of solvate orwater molecules can combine with the compounds according to theinvention to form solvates and hydrates. Unless stated to the contrary,the invention includes all such possible solvates.

It is also appreciated that certain compounds described herein can bepresent as an equilibrium of tautomers. For example, ketones with anα-hydrogen can exist in an equilibrium of the keto form and the enolform.

Likewise, amides with an N-hydrogen can exist in an equilibrium of theamide form and the imidic acid form. Unless stated to the contrary, theinvention includes all such possible tautomers.

It is known that chemical substances form solids which are present indifferent states of order which are termed polymorphic forms ormodifications. The different modifications of a polymorphic substancecan differ greatly in their physical properties. The compounds accordingto the invention can be present in different polymorphic forms, with itbeing possible for particular modifications to be metastable. Unlessstated to the contrary, the invention includes all such possiblepolymorphic forms.

In some aspects, a structure of a compound can be represented by aformula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R^(n) is understood torepresent five independent substituents, R^(n(a)), R^(n(b)), R^(n(c)),R^(n(d)), R^(n(e)). By “independent substituents,” it is meant that eachR substituent can be independently defined. For example, if in oneinstance R^(n(a)) is halogen, then R^(n(b)) is not necessarily halogenin that instance.

Certain materials, compounds, compositions, and components disclosedherein can be obtained commercially or readily synthesized usingtechniques generally known to those of skill in the art. For example,the starting materials and reagents used in preparing the disclosedcompounds and compositions are either available from commercialsuppliers such as Sigma-Aldrich Chemical Co., (Milwaukee, Wis.), AcrosOrganics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), orSigma (St. Louis, Mo.) or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wileyand Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplemental (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition); and Larock'sComprehensive Organic Transformations (VCH Publishers Inc., 1989).

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatan order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; and the number ortype of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions ofthe invention as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds can not be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A-E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including, but not limited to, steps in methods of makingand using the compositions of the invention. Thus, if there are avariety of additional steps that can be performed it is understood thateach of these additional steps can be performed with any specificembodiment or combination of embodiments of the methods of theinvention.

It is understood that the compositions disclosed herein have certainfunctions. Disclosed herein are certain structural requirements forperforming the disclosed functions, and it is understood that there area variety of structures that can perform the same function that arerelated to the disclosed structures, and that these structures willtypically achieve the same result.

B. Compounds

In one aspect, the invention relates to compounds useful as inhibitorsof ENPP1. Moreover, in one aspect, the compounds of the invention areuseful in the treatment of disorders of uncontrolled cellularproliferations. In a further aspect, the disorder of uncontrolledcellular proliferation is a cancer or a tumor. In a still furtheraspect, the disorder of uncontrolled cellular proliferation isassociated with an ENPP1 dysfunction, as further described herein.

In another aspect, the compounds of the invention are useful in thetreatment of diseases of bacterial or viral origin. Accordingly, in oneaspect, the invention provides a method of treating a disease caused bybacteria or viruses, comprising administering to a subject atherapeutically effective amount of a compound of the invention.

It is contemplated that each disclosed derivative can be optionallyfurther substituted. It is also contemplated that any one or morederivative can be optionally omitted from the invention. It isunderstood that a disclosed compound can be provided by the disclosedmethods. It is also understood that the disclosed compounds can beemployed in the disclosed methods of using.

1. Structure

The invention, in one aspect, relates to compounds of Formula I orFormula II:

whereinX is N or CR₁₁;Y is selected from the group consisting of —CR₄R₅—, —NR₆—,—N(CH₂)_(m)O—, —O—, —S—, —S(O)—, —S(O)₂, aryl, and heteroaryl; wherein mis 2 or 3;L is selected from the group consisting of an C₁-C₅ alkyl, and C₁-C₅alkenyl;each R₁, R₂ and R₃ are independently selected from the group consistingof hydrogen, halogen, CN, OR^(a), —C(═O)NR^(b)R^(c), —NR^(b)R^(c),—C(═O)R^(d), aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.each R^(a) is independently selected from the group consisting ofhydrogen, lower alkyl, —(CH₂)_(n)—C(═O)NR^(b)R^(c), aralkyl, aryl,heteroaryl, heterocycloalkyl, and cycloalkyl;wherein n is an integer between 1 and 3;each R^(b) and R^(c) is independently selected from the group consistingof hydrogen, a lower alkyl, and lower aryl, heterocycloalkyl, orcycloalkyl;each R^(d) is independently selected from the group consisting of—OR^(e) and lower alkyl;each R^(e) is independently selected from the group consisting ofhydrogen, a lower alkyl, and a lower aryl;R₁₁ is independently selected from the group consisting of hydrogen,halogen, COOEt, COOH, and CN;R₄, R₅ and R₆ are independently selected from the group consisting ofhydrogen and lower alkyl;or an isomer, hydrate, solvate, polymorph, tautomer or apharmaceutically acceptable salt thereof.

A compound of Formula II is as follows:

whereinX is N or CR₁₁;Z is C or N;W is selected from the group consisting of an C₁-C₅ alkyl,—C(═O)—(CH₂)_(n)—, —(C₁-C₅ alkyl)-N—; NH, and a direct bond as follows:

each R₁, R₂ and R₃ are independently selected from the group consistingof hydrogen, halogen, CN, OR^(a), —C(═O)NR^(b)R^(c), —NR^(b)R^(c),—C(═O)R^(d), aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.each R^(a) is independently selected from the group consisting ofhydrogen, lower alkyl, and —(CH₂)_(n)—C(═O)NR^(b)R^(c), aralkyl, aryl,heteroaryl, heterocycloalkyl, cycloalkyl;wherein n is an integer between 1 and 3;each R^(b) and R^(c) is independently selected from the group consistingof hydrogen, a lower alkyl, and lower aryl, heterocycloalkyl, orcycloalkyl;each R^(d) is independently selected from the group consisting of—OR^(e) and lower alkyl;each R^(e) is independently selected from the group consisting ofhydrogen, a lower alkyl, and a lower aryl;R₁₁ is independently selected from the group consisting of hydrogen,halogen, COOEt, COOH, and CN;R₇, R₈ and R₉ are independently selected from the group consisting of H,halogen and lower alkyl; and R₈ and R₉ can also form a bridge across the7-membered ring with 1 or 2 atoms, as follows:

R₁₀ is independently selected from the group consisting of hydrogen andCF₃;or an isomer, hydrate, solvate, polymorph, tautomer or apharmaceutically acceptable salt thereof.

The invention encompasses any compounds or structures that include anycombinations of the substituents as defined above.

In one preferred embodiment, Y in Formula I is pyridinyl.

In one preferred embodiment, X in Formula I or Formula II is C—CN.

In one preferred embodiment, Y in Formula I is NR₆.

In one preferred embodiment, in compounds of Formula I and Formula II,R₁, R₂ and R₃ are selected from the group consisting of CH₃O and H.

In one preferred embodiment, in compounds of Formula II, Z is N.

In one preferred embodiment, in compounds of Formula II, W is selectedfrom the group consisting of -4,5-imidazole, 2-Oxazole, 3-pyrrole;pyrazole, and thiazole.

In one preferred embodiment, in compounds of Formula II, X is N.

In one preferred embodiment, in compounds of Formula II, X is C—CN.

In one preferred embodiment, in compounds of Formula II, R₇, R₈ and R₉are independently selected from the group consisting of H and halogen.

In one preferred embodiment, in compounds of Formula II, R₇ is ahalogen, and more preferably F.

In one preferred embodiment, in compounds of Formula II, R₈ and R₉ areboth halogen.

In one preferred embodiment,

the compound is of Formula I;

X is N;

Y is selected from the group consisting of pyridinyl, C₁-C₅ alkyl, O, N,and S;

L is an optionally substituted C₁-C₅ alkyl; and

R₁ and R₂ are both CH₃O.

In another preferred embodiment,

the compound is of Formula II;

X is N;

Z is N;

W is selected from the group consisting of an optionally substitutedC₁-C₅ alkyl, —C(═O)—(CH₂)—, —(an optionally substituted C₁-C₅ alkyl)-N;and a direct bond; and

R₁ and R₂ are both CH₃O.

Examples of the provided compounds include:

The invention also provides a pharmaceutical composition comprising atherapeutically effective amount of any of a compound of the inventionand a pharmaceutically acceptable carrier.

The invention also provides a method for the treatment of a disorder ofuncontrolled cellular proliferation in a mammal, the method comprisingthe step of administering to the mammal an effective amount of any ofthe compounds of the invention.

The invention also provides a method for decreasing ENPP1 activity in amammal, the method comprising the step of administering to the mammal aneffective amount of any of the compounds of the invention.

The invention also provides a method for inhibiting ENPP1 activity in amammal, the method comprising the step of administering to the mammal aneffective amount of any of the compounds of the invention.

C. Methods of Making the Compounds

In one aspect, the invention relates to methods of making compoundsuseful as inhibitors of ENPP1. In a further aspect, the products ofdisclosed methods of making are modulators of ENPP1 activity.

The compounds of this invention can be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature, exemplified in theexperimental sections or clear to one skilled in the art. For clarity,examples having a single substituent are shown where multiplesubstituents are allowed under the definitions disclosed herein.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the following Reaction Schemes, inaddition to other standard manipulations known in the literature or toone skilled in the art. The following examples are provided so that theinvention might be more fully understood, are illustrative only, andshould not be construed as limiting.

In one aspect, the disclosed compounds comprise the products of thesynthetic methods described herein. In a further aspect, the disclosedcompounds comprise a compound produced by a synthetic method describedherein. In a still further aspect, the invention comprises apharmaceutical composition comprising a therapeutically effective amountof the product of the disclosed methods and a pharmaceuticallyacceptable carrier. In a still further aspect, the invention comprises amethod for manufacturing a medicament comprising combining at least onecompound of any of disclosed compounds or at least one product of thedisclosed methods with a pharmaceutically acceptable carrier or diluent.

Where reaction conditions and amounts of ingredients are not stated, itis believed that it is within a skill in the art to determine them. Itis contemplated that each disclosed methods can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood thatdisclosed methods can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

D. Pharmaceutical Compositions

In one aspect, the invention relates to pharmaceutical compositionscomprising the disclosed compounds. That is, a pharmaceuticalcomposition can be provided comprising a therapeutically effectiveamount of at least one disclosed compound or at least one product of adisclosed method and a pharmaceutically acceptable carrier.

In a further aspect, the invention relates to pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and aneffective amount of the product of a disclosed synthetic method. In afurther aspect, the effective amount is a therapeutically effectiveamount. In a further aspect, the effective amount is a prophylacticallyeffective amount. In a further aspect, the compound is a disclosedcompound.

In certain aspects, the disclosed pharmaceutical compositions comprisethe disclosed compounds (including pharmaceutically acceptable salt(s)thereof) as an active ingredient, a pharmaceutically acceptable carrier,and, optionally, other therapeutic ingredients or adjuvants. The instantcompositions include those suitable for oral, rectal, topical, andparenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions can be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts prepared from pharmaceutically acceptable non-toxic bases oracids. When the compound of the present invention is acidic, itscorresponding salt can be conveniently prepared from pharmaceuticallyacceptable non-toxic bases, including inorganic bases and organic bases.Salts derived from such inorganic bases include aluminum, ammonium,calcium, copper (-ic and -ous), ferric, ferrous, lithium, magnesium,manganese (-ic and -ous), potassium, sodium, zinc and the like salts.Particularly preferred are the ammonium, calcium, magnesium, potassiumand sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, as well as cyclic amines and substituted amines such asnaturally occurring and synthesized substituted amines. Otherpharmaceutically acceptable organic non-toxic bases from which salts canbe formed include ion exchange resins such as, for example, arginine,betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

As used herein, the term “pharmaceutically acceptable non-toxic acids”,includes inorganic acids, organic acids, and salts prepared therefrom,for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

In practice, the compounds of the invention, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier can take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compounds of theinvention, and/or pharmaceutically acceptable salt(s) thereof, can alsobe administered by controlled release means and/or delivery devices. Thecompositions can be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention can include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of the compounds of the invention. The compounds of theinvention, or pharmaceutically acceptable salts thereof, can also beincluded in pharmaceutical compositions in combination with one or moreother therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media can be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likecan be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like can be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets can be coated by standard aqueous or nonaqueoustechniques.

A tablet containing the composition of this invention can be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets can be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent.

The pharmaceutical compositions of the present invention comprise acompound of the invention (or pharmaceutically acceptable salts thereof)as an active ingredient, a pharmaceutically acceptable carrier, andoptionally one or more additional therapeutic agents or adjuvants. Theinstant compositions include compositions suitable for oral, rectal,topical, and parenteral (including subcutaneous, intramuscular, andintravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions can be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Pharmaceutical compositions of the present invention suitable forparenteral administration can be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, mouth washes, gargles, and the like.Further, the compositions can be in a form suitable for use intransdermal devices. These formulations can be prepared, utilizing acompound of the invention, or pharmaceutically acceptable salts thereof,via conventional processing methods. As an example, a cream or ointmentis prepared by mixing hydrophilic material and water, together withabout 5 wt % to about 10 wt % of the compound, to produce a cream orointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories can be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above can include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound of the invention, and/or pharmaceuticallyacceptable salts thereof, can also be prepared in powder or liquidconcentrate form.

In the treatment conditions which require inhibition or negativemodulation of ENPP1 protein activity an appropriate dosage level willgenerally be about 0.01 to 500 mg per kg patient body weight per day andcan be administered in single or multiple doses. Preferably, the dosagelevel will be about 0.1 to about 250 mg/kg per day; more preferably 0.5to 100 mg/kg per day. A suitable dosage level can be about 0.01 to 250mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kgper day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5.0 or5.0 to 50 mg/kg per day. For oral administration, the compositions arepreferably provided in the from of tablets containing 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20,25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and1000 milligrams of the active ingredient for the symptomatic adjustmentof the dosage of the patient to be treated. The compound can beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day. This dosing regimen can be adjusted to provide theoptimal therapeutic response.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors. Such factorsinclude the age, body weight, general health, sex, and diet of thepatient. Other factors include the time and route of administration,rate of excretion, drug combination, and the type and severity of theparticular disease undergoing therapy.

The present invention is further directed to a method for themanufacture of a medicament for inhibiting or negatively modulatingENPP1 protein activity (e.g., treatment of a disorder of uncontrolledcellular proliferation, or one or more neurodegenerative disordersassociated with ENPP1 dysfunction) in mammals (e.g., humans) comprisingcombining one or more disclosed compounds, products, or compositionswith a pharmaceutically acceptable carrier or diluent. Thus, in oneaspect, the invention relates to a method for manufacturing a medicamentcomprising combining at least one disclosed compound or at least onedisclosed product with a pharmaceutically acceptable carrier or diluent.

The disclosed pharmaceutical compositions can further comprise othertherapeutically active compounds, which are usually applied in thetreatment of the above-mentioned pathological conditions.

It is understood that the disclosed compositions can be prepared fromthe disclosed compounds. It is also understood that the disclosedcompositions can be employed in the disclosed methods of using.

E. Methods of Using the Compounds and Compositions

The disclosed compounds can be used as single agents or in combinationwith one or more other drugs in the treatment, prevention, control,amelioration or reduction of risk of the aforementioned diseases,disorders and conditions for which compounds of formulas I or II or theother drugs have utility, where the combination of drugs together aresafer or more effective than either drug alone. The other drug(s) can beadministered by a route and in an amount commonly used therefore,contemporaneously or sequentially with a disclosed compound. When adisclosed compound is used contemporaneously with one or more otherdrugs, a pharmaceutical composition in unit dosage form containing suchdrugs and the disclosed compound is preferred. However, the combinationtherapy can also be administered on overlapping schedules. It is alsoenvisioned that the combination of one or more active ingredients and adisclosed compound will be more efficacious than either as a singleagent.

The pharmaceutical compositions and methods of the present invention canfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above-mentionedpathological conditions.

1. Treatment Methods

The compounds disclosed herein are useful for treating, preventing,ameliorating, controlling or reducing the risk of a variety of disorderswherein the patient or subject would benefit from inhibition or negativemodulation of ENPP1. In one aspect, provided is a method of treating orpreventing a disorder in a subject comprising the step of administeringto the subject at least one disclosed compound; at least one disclosedpharmaceutical composition; and/or at least one disclosed product in adosage and amount effective to treat the disorder in the subject.

Also provided is a method for the treatment of one or more disorders,for which ENPP1 inhibition is predicted to be beneficial, in a subjectcomprising the step of administering to the subject at least onedisclosed compound; at least one disclosed pharmaceutical composition;and/or at least one disclosed product in a dosage and amount effectiveto treat the disorder in the subject.

In one aspect, provided is a method for treating a disorder ofuncontrolled cellular proliferation, comprising: administering to asubject at least one disclosed compound; at least one disclosedpharmaceutical composition; and/or at least one disclosed product in adosage and amount effective to treat the disorder in the subject. In afurther aspect, provided is a method for treating or preventing aneurodegenerative disorder, comprising: administering to a subject atleast one disclosed compound; at least one disclosed pharmaceuticalcomposition; and/or at least one disclosed product in a dosage andamount effective to treat the disorder in the subject. Also provided isa method for the treatment of a disorder in a mammal comprising the stepof administering to the mammal at least one disclosed compound,composition, or medicament.

The invention is directed at the use of described chemical compositionsto treat diseases or disorders in patients (preferably human) whereinENPP1 inhibition would be predicted to have a therapeutic effect, suchas disorders of uncontrolled cellular proliferation (e.g. cancers) andneurodegenerative disorders such as Alzheimer's disease, Huntington'sdisease, and Parkinson's disease, diseases caused by bacteria and/orviruses (including DNA and RNA viruses), by administering one or moredisclosed compounds or products.

The compounds of the invention can also be used for immunotherapy. Inone embodiment, the compounds of the invention treat disorders ofuncontrolled cellular proliferation, and/or diseases caused by bacteriaand/or viruses through immunotherapy, meaning that the compounds elicitimmunotherapeutic response which results in the treatment of thesediseases.

The compounds disclosed herein are useful for treating, preventing,ameliorating, controlling or reducing the risk of a variety of disordersof uncontrolled cellular proliferation.

Also provided is a method of use of a disclosed compound, composition,or medicament. In one aspect, the method of use is directed to thetreatment of a disorder. In a further aspect, the disclosed compoundscan be used as single agents or in combination with one or more otherdrugs in the treatment, prevention, control, amelioration or reductionof risk of the aforementioned diseases, disorders and conditions forwhich the compound or the other drugs have utility, where thecombination of drugs together are safer or more effective than eitherdrug alone. The other drug(s) can be administered by a route and in anamount commonly used therefore, contemporaneously or sequentially with adisclosed compound. When a disclosed compound is used contemporaneouslywith one or more other drugs, a pharmaceutical composition in unitdosage form containing such drugs and the disclosed compound ispreferred. However, the combination therapy can also be administered onoverlapping schedules. It is also envisioned that the combination of oneor more active ingredients and a disclosed compound can be moreefficacious than either as a single agent.

Examples of disorders treatable with the provided compounds include adisorder of uncontrolled cellular proliferation. In a yet furtheraspect, the disorder of uncontrolled cellular proliferation is cancer.In a yet further aspect, the cancer is a leukemia. In an even furtheraspect, the cancer is a sarcoma. In a still further aspect, the canceris a solid tumor. In a yet further aspect, the cancer is a lymphoma.

It is understood that cancer refer to or describe the physiologicalcondition in mammals that is typically characterized by unregulated cellgrowth. The cancer may be multi-drug resistant (MDR) or drug-sensitive.Examples of cancer include but are not limited to, carcinoma, lymphoma,blastoma, sarcoma, and leukemia. More particular examples of suchcancers include breast cancer, prostate cancer, colon cancer, squamouscell cancer, small-cell lung cancer, non-small cell lung cancer,gastrointestinal cancer, pancreatic cancer, cervical cancer, ovariancancer, peritoneal cancer, liver cancer, e.g., hepatic carcinoma,bladder cancer, colorectal cancer, endometrial carcinoma, kidney cancer,and thyroid cancer.

In various aspects, further examples of cancers are basal cellcarcinoma, biliary tract cancer; bone cancer; brain and CNS cancer;choriocarcinoma; connective tissue cancer; esophageal cancer; eyecancer; cancer of the head and neck; gastric cancer; intra-epithelialneoplasm; larynx cancer; lymphoma including Hodgkin's and Non-Hodgkin'slymphoma; melanoma; myeloma; neuroblastoma; oral cavity cancer (e.g.,lip, tongue, mouth, and pharynx); retinoblastoma; rhabdomyosarcoma;rectal cancer; cancer of the respiratory system; sarcoma; skin cancer;stomach cancer; testicular cancer; uterine cancer; cancer of the urinarysystem, as well as other carcinomas and sarcomas

In a further aspect, the cancer is a hematological cancer. In a stillfurther aspect, the hematological cancer is selected from acute myeloidleukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloidleukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia,chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia(JMML), Hodgkin lymphoma, Non-Hodgkin lymphoma, multiple myeloma,solitary myeloma, localized myeloma, and extramedullary myeloma. In astill further aspect, the cancer is selected from chronic lymphocyticleukemia, small lymphocytic lymphoma, B-cell non-Hodgkin lymphoma, andlarge B-cell lymphoma.

In a further aspect, the cancer is a cancer of the brain. In a stillfurther aspect, the cancer of the brain is selected from a glioma,medulloblastoma, primitive neuroectodermal tumor (PNET), acousticneuroma, glioma, meningioma, pituitary adenoma, schwannoma, CNSlymphoma, primitive neuroectodermal tumor, craniopharyngioma, chordoma,medulloblastoma, cerebral neuroblastoma, central neurocytoma,pineocytoma, pineoblastoma, atypical teratoid rhabdoid tumor,chondrosarcoma, chondroma, choroid plexus carcinoma, choroid plexuspapilloma, craniopharyngioma, dysembryoplastic neuroepithelial tumor,gangliocytoma, germinoma, hemangioblastoma, hemangiopercytoma, andmetastatic brain tumor. In a yet further aspect, the glioma is selectedfrom ependymoma, astrocytoma, oligodendroglioma, and oligoastrocytoma.In an even further aspect, the glioma is selected from juvenilepilocytic astrocytoma, subependymal giant cell astrocytoma,ganglioglioma, subependymoma, pleomorphic xanthoastrocytom, anaplasticastrocytoma, glioblastoma multiforme, brain stem glioma,oligodendroglioma, ependymoma, oligoastrocytoma, cerebellar astrocytoma,desmoplastic infantile astrocytoma, subependymal giant cell astrocytoma,diffuse astrocytoma, mixed glioma, optic glioma, gliomatosis cerebri,multifocal gliomatous tumor, multicentric glioblastoma multiforme tumor,paraganglioma, and ganglioglioma.

In one aspect, the cancer can be a cancer selected from cancers of theblood, brain, genitourinary tract, gastrointestinal tract, colon,rectum, breast, kidney, lymphatic system, stomach, lung, pancreas, andskin. In a further aspect, the cancer is selected from prostate cancer,glioblastoma multiforme, endometrial cancer, breast cancer, and coloncancer. In a further aspect, the cancer is selected from a cancer of thebreast, ovary, prostate, head, neck, and kidney. In a still furtheraspect, the cancer is selected from cancers of the blood, brain,genitourinary tract, gastrointestinal tract, colon, rectum, breast,livery, kidney, lymphatic system, stomach, lung, pancreas, and skin. Ina yet further aspect, the cancer is selected from a cancer of the lungand liver. In an even further aspect, the cancer is selected from acancer of the breast, ovary, testes and prostate. In a still furtheraspect, the cancer is a cancer of the breast. In a yet further aspect,the cancer is a cancer of the ovary. In an even further aspect, thecancer is a cancer of the prostate. In a still further aspect, thecancer is a cancer of the testes.

In various aspects, disorders associated with an ENPP1 dysfunctioninclude neurodegenerative disorders. In a further aspect, theneurodegenerative disease is selected from Alzheimer's disease,Parkinson's disease, and Huntington's disease.

The compounds are further useful in a method for the prevention,treatment, control, amelioration, or reducation of risk of the diseases,disorders and conditions noted herein. The compounds are further usefulin a method for the prevention, treatment, control, amelioration, orreduction of risk of the aforementioned diseases, disorders andconditions in combination with other agents.

The present invention is further directed to administration of an ENPP1inhibitor for improving treatment outcomes in the context of disordersof uncontrolled cellular proliferation, including cancer. That is, inone aspect, the invention relates to a cotherapeutic method comprisingthe step of administering to a mammal an effective amount and dosage ofat least one compound of the invention in connection with cancertherapy.

In a further aspect, administration improves treatment outcomes in thecontext of cancer therapy. Administration in connection with cancertherapy can be continuous or intermittent. Administration need not besimultaneous with therapy and can be before, during, and/or aftertherapy. For example, cancer therapy can be provided within 1, 2, 3, 4,5, 6, 7 days before or after administration of the compound. As afurther example, cancer therapy can be provided within 1, 2, 3, or 4weeks before or after administration of the compound. As a still furtherexample, cognitive or behavioral therapy can be provided before or afteradministration within a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 half-lives of the administered compound.

In one aspect, the disclosed compounds can be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichdisclosed compounds or the other drugs can have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) can be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and a disclosed compound is preferred. However, thecombination therapy can also include therapies in which a disclosedcompound and one or more other drugs are administered on differentoverlapping schedules. It is also contemplated that when used incombination with one or more other active ingredients, the disclosedcompounds and the other active ingredients can be used in lower dosesthan when each is used singly. In one embodiment, the invention isdirected to a combination therapy wherein a compound of Formula I orFormula II is used together with radiation therapy. Radiation therapycan be conducted simultaneously, prior or after administering a compoundof the present invention.

Accordingly, the pharmaceutical compositions include those that containone or more other active ingredients, in addition to a compound of thepresent invention.

The above combinations include combinations of a disclosed compound notonly with one other active compound, but also with two or more otheractive compounds. Likewise, disclosed compounds can be used incombination with other drugs that are used in the prevention, treatment,control, amelioration, or reduction of risk of the diseases orconditions for which disclosed compounds are useful. Such other drugscan be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to a disclosedcompound is preferred. Accordingly, the pharmaceutical compositionsinclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention.

The weight ratio of a disclosed compound to the second active ingredientcan be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the present invention is combined withanother agent, the weight ratio of a disclosed compound to the otheragent will generally range from about 1000:1 to about 1:1000, preferablyabout 200:1 to about 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

In such combinations a disclosed compound and other active agents can beadministered separately or in conjunction. In addition, theadministration of one element can be prior to, concurrent to, orsubsequent to the administration of other agent(s).

Accordingly, the subject compounds can be used alone or in combinationwith other agents which are known to be beneficial in the subjectindications or other drugs that affect receptors or enzymes that eitherincrease the efficacy, safety, convenience, or reduce unwanted sideeffects or toxicity of the disclosed compounds. The subject compound andthe other agent can be coadministered, either in concomitant therapy orin a fixed combination.

In one aspect, the compound can be employed in combination withanti-cancer therapeutic agents or other known therapeutic agents.

In the treatment of conditions which require inhibition or negativemodulation of ENPP1, an appropriate dosage level will generally be about0.01 to 1000 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.1 to about 250 mg/kg per day; more preferably about 0.5to about 100 mg/kg per day. A suitable dosage level can be about 0.01 to250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50mg/kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5or 5 to 50 mg/kg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20,25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and1000 milligrams of the active ingredient for the symptomatic adjustmentof the dosage to the patient to be treated. The compounds can beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day. This dosage regimen can be adjusted to provide theoptimal therapeutic response. It will be understood, however, that thespecific dose level and frequency of dosage for any particular patientcan be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular condition, and the hostundergoing therapy.

Thus, in one aspect, the invention relates to methods for inhibiting ornegatively modulating ENPP1 in at least one cell, comprising the step ofcontacting the at least one cell with at least one compound of theinvention, in an amount effective to modulate or activate ENPP1 activityresponse, e.g. in the at least one cell. In a further aspect, the cellis mammalian, for example human. In a further aspect, the cell has beenisolated from a subject prior to the contacting step. In a furtheraspect, contacting is via administration to a subject.

a. Treatment of a Disorder of Uncontrolled Cellular Proliferation

In one aspect, the invention relates to a method for the treatment of adisorder of uncontrolled cellular proliferation in a mammal, the methodcomprising the step of administering to the mammal an effective amountof least one disclosed compound or a product of a disclosed method ofmaking a compound, or a pharmaceutically acceptable salt, hydrate,solvate, or polymorph thereof, thereby treating the disorder ofuncontrolled cellular proliferation.

In a still further aspect, the effective amount is a therapeuticallyeffective amount. In a yet still further aspect, the effective amount isa prophylactically effective amount.

In a further aspect, the mammal is a human. In a yet further aspect, themethod further comprises the step of identifying a mammal in need oftreatment of a disorder of uncontrolled cellular proliferation. In astill further aspect, the mammal has been diagnosed with a need fortreatment of a disorder of uncontrolled cellular proliferation prior tothe administering step.

In a further aspect, the disorder of uncontrolled cellular proliferationis a cancer. In a yet further aspect, the cancer is a leukemia. In aneven further aspect, the cancer is a sarcoma. In a still further aspect,the cancer is a solid tumor. In a yet further aspect, the cancer is alymphoma. In an even further aspect, the cancer is selected from chroniclymphocytic leukemia, small lymphocytic lymphoma, B-cell non-Hodgkinlymphoma, and large B-cell lymphoma. In a still further aspect, thecancer is selected from cancers of the blood, brain, genitourinarytract, gastrointestinal tract, colon, rectum, breast, livery, kidney,lymphatic system, stomach, lung, pancreas, and skin. In a yet furtheraspect, the cancer is selected from a cancer of the lung and liver. Inan even further aspect, the cancer is selected from a cancer of thebreast, ovary, testes and prostate. In a still further aspect, thecancer is a cancer of the breast. In a yet further aspect, the cancer isa cancer of the ovary. In an even further aspect, the cancer is a cancerof the prostate. In a still further aspect, the cancer is a cancer ofthe testes.

EXAMPLES F. Experimental

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Starting materials and therequisite intermediates are in some cases commercially available, or canbe prepared according to literature procedures or as illustrated herein.

The following exemplary compounds of the invention were synthesized. TheExamples are provided herein to illustrate the invention, and should notbe construed as limiting the invention in any way. The Examples aretypically depicted in free base form, according to the IUPAC namingconvention. However, some of the Examples were obtained or isolated insalt form.

Some of the Examples were obtained as racemic mixtures of one or moreenantiomers or diastereomers. The compounds may be separated by oneskilled in the art to isolate individual enantiomers. Separation can becarried out by the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. A racemicor diastereomeric mixture of the compounds can also be separateddirectly by chromatographic methods using chiral stationary phases.

Experimental Chemistry Synthesis Schemes, Methods and Procedures

Example 1: Synthesis of (N-(3-((6, 7-dimethoxyquinazolin-4-yl) oxy)propyl) sulfamide) Step 1: Synthesis of Tert-butyl (N-(3-hydroxypropyl)sulfamoyl) carbamate

To a stirred solution of 3-aminopropan-1-ol 1 (500 mg, 6.666 mmol) indichloromethane (20 ml) were added diisopropylethylamine (1.9 mL, 9.999mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium2 (2.25 g, 7.385 mmol) at 0° C. then stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After completionof the reaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified through100-200 silica gel column chromatography by eluting 3% methanol indichloromethane to afford semi pure compound. This semi pure was washedwith 50% ethyl acetate in pet ether to afford tert-butyl(N-(3-hydroxypropyl) sulfamoyl) carbamate 3 (650 mg, 2.559 mmol, 38%yield) as an off-white solid.

1H NMR (400 MHz, DMSO) δ 10.77 (s, 1H), 7.45 (t, 1H), 4.44 (t, 1H), 3.40(d, 2H), 2.91 (d, 2H), 1.60-1.57 (t, 2H), 1.41 (s, 9H)

The following compounds were synthesized by using the above generalprocedure.

Structure Yield (%) 1HNMR

14 (400 MHz, DMSO) δ 10.75 (s, 1H), 7.52 (t, 1H), 4.38 (t, 1H), 3.35 (m,2H), 2.85 (m, 2H), 1.46 (m, 4H), 1.41 (s, 9H).

53 (400 MHz, DMSO) δ 10.76 (s, 1H), 7.51 (t, 1H), 4.34 (t, 1H), 3.35 (m,2H), 2.84 (m, 2H), 1.45-1.35 (m, 11H), 1.26 (m, 4H).

Step 2: Synthesis of Tert-butyl (N-(3-((6, 7-dimethoxyquinazolin-4-yl)oxy) propyl) sulfamoyl) carbamate

To a stirred solution of tert-butyl (N-(3-hydroxypropyl) sulfamoyl)carbamate 4 (900 mg, 3.897 mmol) in dichloromethane (20 ml) was added60% NaH (212 mg, 5.314 mmol) and then stirred at reflux for 30 minutes.Then added 4-chloro-6, 7-dimethoxyquinazoline 3 (795 mg, 3.542 mmol) atroom temperature again stirred at reflux for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, to thereaction mixture was added water (200 mL) and extracted with ethylacetate (2×100 mL). Combined organic layers were washed with brinesolution (100 mL), dried over sodium sulfate and concentrated underreduced pressure. Crude compound was purified through 100-200 silica gelcolumn chromatography by eluting 100% ethyl acetate to afford tert-butyl(N-(3-((6, 7-dimethoxyquinazolin-4-yl) oxy) propyl) sulfamoyl) carbamate5 (700 mg, 1.583 mmol, 44% yield) as a pale yellow solid. 1H NMR (400MHz, DMSO) δ 10.85 (s, 1H), 8.60 (s, 1H), 7.71 (s, 1H), 7.31 (d, 2H),4.55 (t, 2H), 3.92 (d, 6H), 3.12 (d, 2H), 2.01 (m, 2H), 1.37 (s, 9H).LC-MS: M/Z: 442.9 (M+1)

The following compounds were synthesized by using the above generalprocedure.

Structure 1HNMR

(400 MHz, DMSO) δ 10.79 (s, 1H), 8.60 (s, 1H), 7.63 (bs, 1H), 7.30 (d,2H), 4.50 (t, 2H), 3.92 (d, 6H), 2.97 (d, 2H), 1.86 (d, 2H), 1.65 (d,2H), 1.37 (s, 9H). MS 456.9

(400 MHz, DMSO) δ 10.86- 10.67 (bs, 1H), 8.60 (s, 1H), 7.51 (bs, 1H),7.30 (s, 1H), 7.29 (s, 1H) 4.50 (t, 2H), 3.91 (s, 3H), 3.94 (s, 3H) 2.89(d, 2H), 1.83-1.79 (m, 2H), 1.54-1.47 (m, 4H), 1.38 (s, 9H). MS 471.2

Step 3: Synthesis of(N-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)propyl)sulfamide)

To a stirred solution of tert-butyl(N-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)propyl)sulfamoyl)carbamate (200mg, 0.452 mmol) in 1,4-dioxane (2 ml) was added 4M HCl in Dioxane (8 mL)at 0° C. then stirred at room temperature for 3 h. The progress of thereaction was monitored by TLC. After completion of the reaction, organicsolvents completely distilled off under reduced pressure to afford crudecompound. Crude compound was purified through prep HPLC method to affordpure compound of(N-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)propyl)sulfamide) (Target-12)(120 mg, 0.35 mmol, 78% yield) as a pale yellow solid. 1H NMR (400 MHz,DMSO) δ 8.93 (s, 1H), 7.42 (d, 2H), 6.57 (bs, 2H), 4.67 (t, 2H), 3.96(d, 6H), 3.10 (t, 2H), 2.06 (t, 2H).

The following compounds were synthesized by using the above generalprocedure.

Compound Number Structure 1HNMR 053

(400 MHz, DMSO) δ 8.60 (s, 1H), 7.30 (d, 2H), 6.48- 6.38 (m, 3H), 4.51(t, 2H), 3.92 (d, 6H), 2.89 (t, 2H), 1.87-1.78 (m, 2H), 1.59- 1.44 (m,4H). 054

(400 MHz, DMSO) δ 8.61 (s, 1H), 7.31 (d, 2H), 6.48 (s, 2H), 6.53 (t, 1H)4.52 (t, 2H), 3.91 (s, 3H), 3.94 (s, 3H) 2.95 (m, 2H), 1.90- 1.85 (t,2H), 1.67 (t, 2H).

Compound 052 was also prepared based on the general procedure of Example1.

1H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 7.42 (d, 2H), 6.57 (bs, 2H), 4.67(t, 2H), 3.96 (d, 6H), 3.10 (t, 2H), 2.06 (t, 2H). LCMS 342.9; MW378.83.

Example 2: N-(3-((6, 7-dimethoxyquinazolin-4-yl) amino) propyl sulfamidehydrochloride Step 1: N1-(6, 7-dimethoxyquinazolin-4-yl) propane-1,3-diamine

To a stirred solution of 4-chloro-6, 7-dimethoxyquinazoline (2 g, 8.9mmol) in tetrahydrofuran (20 ml) was added propane-1, 3-diamine (3.7 mL,44.50 mmol) at room temperature and stirred the reaction mixture at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, organic solvents completely distilledoff under reduced pressure to afford crude compound. Crude compound waspurified through Grace reverse phase chromatography by eluting 40%acetonitrile in water to afford pure compound of N1-(6,7-dimethoxyquinazolin-4-yl) propane-1, 3-diamine (500 mg, 1.908 mmol,21% yield) as a light brown solid. 1H NMR (400 MHz, DMSO) 8.3 (s, 1H),8.0 (brs, 1H), 7.57 (s, 1H), 7.05 (s, 1H), 3.86 (s, 6H), 3.55-3.46 (m,2H), 2.64 (t, 3H), 1.75-1.68 (m, 2H).

1.98 (s, 2H), 1.15 (d, 9H).

The following compounds were synthesized by using the above generalprocedures.

Structure 1HNMR

(400 MHz, DMSO) 8.3 (s, 1H), 7.95 (s, 1H), 7.56 (s, 1H), 7.05 (s, 1H),3.86 (s, 6H), 3.49-3.48 (m, 2H), 2.56 (t, 2H), 1.65-1.62 (m, 2H),1.44-1.40 (m, 2H). MS 277.1

(400 MHz, DMSO) 8.3 (s, 1H), 7.89 (brs, 1H), 7.57 (s, 1H), 7.05 (s, 1H),3.86 (s, 6H), 3.49-3.47 (m, 2H), 2.53 (m, 2H), 1.63-1.62 (m, 2H), 1.37-1.31 (m, 4H).

(400 MHz, DMSO) δ 8.31 (s, 1H), 8.00 (t, 1H), 7.59 (s, 1H), 7.06 (s,1H), 3.87 (d, 6H), 3.70-3.66 (m, 2H), 3.60 (t, 2H), 3.38 (m, 2H), 2.64(t, 2H).

Step 2: Synthesis of Tert-butyl (N-(3-((6, 7-dimethoxyquinazolin-4-yl)amino) propyl) sulfamoyl) carbamate

To a stirred solution ofN1-(6,7-dimethoxyquinazolin-4-yl)propane-1,3-diamine (500 mg, 1.90 mmol)in dichloromethane (40 ml) were added diisopropylethylamine (1.65 mL,9.50 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminiumchloride (640 mg, 1.90 mmol) at RT, then stirred at room temperature for16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, organic solvents completely distilled offunder reduced pressure to afford crude compound. Crude compound waspurified combi flash column chromatography by eluting 2% methanol indichloromethane to afford tert-butyl (N-(3-((6,7-dimethoxyquinazolin-4-yl) amino) propyl) sulfamoyl) carbamate (600 mg,1.36 mmol, 71% yield) as a yellow solid. 1H NMR (400 MHz, DMSO) 10.83(s, 1H), 8.31 (s, 1H), 7.89 (t, 1H), 7.60 (s, 1H), 7.54 (s, 1H), 7.06(s, 1H) 3.87 (s, 6H), 3.55-3.50 (m, 2H), 2.98-2.93 (m, 2H), 1.82 (t,2H), 1.36 (s, 9H). LCMS: (M+H+): m/Z: 441.9

The following compounds were synthesized by the above general procedure

Structure 1HNMR

(400 MHz, DMSO) 10.79 (s, 1H), 8.3 (s, 1H), 7.88 (s, 1H), 7.57-7.56 (s,2H), 7.05 (s, 1H), 3.87 (s, 6H), 3.49-3.48 (m, 2H), 2.92 (t, 2H),1.64-1.62 (m, 2H), 1.54-1.50 (m, 2H), 1.38 (s, 6H). MS 455.9

(400 MHz, DMSO) 10.79 (brs, 1H), 8.3 (s, 1H), 7.88 (brs, 1H), 7.56-7.53(m, 2H), 7.05 (s, 1H), 3.86 (s, 6H), 3.48-3.47 (m, 2H), 2.88-2.86 (m,2H), 1.62-1.59 (m, 2H), 1.39-1.35 (m, 11H). 469.9

(400 MHz, DMSO) δ 10.99- 10.73 (m, 1H), 8.72-8.55 (m, 1H), 8.34 (s, 1H),8.06 (s, 1H), 7.62 (s, 1H), 7.54 (t, 1H), 7.07 (s, 1H), 3.88 (s, 6H),3.72-3.66 (m, 2H), 3.65-3.55 (m, 4H), 3.50 (t, 2H), 3.14 (m, 2H), 3.05(m, 2H), 1.37 (s, 8H). MS 472.2

Step 3: Synthesis of N-(3-((6, 7-dimethoxyquinazolin-4-yl) amino)propyl) sulfamide hydrochloride

To a stirred solution of tert-butyl(N-(3-((6,7-dimethoxyquinazolin-4-yl)amino)propyl)sulfamoyl)carbamate(200 mg, 0.453 mmol) in 1,4-dioxane (0.5 ml) was added 4M HCl in dioxane(2 mL) at RT, then stirred at 50° C. for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, organicsolvents completely distilled off under reduced pressure to afford crudecompound. Crude compound was purified through prep HPLC to afford purecompound of (N-(3-((6,7-dimethoxyquinazolin-4-yl)amino)propyl)sulfamidehydrochloride (100 mg, 0.293 mmol, 65% yield) as an off white solid. 1HNMR (400 MHz, DMSO) 14.42 (brs, 1H), 9.99 (s, 1H), 8.79 (s, 1H), 8.02(s, 1H), 7.23 (s, 1H), 6.61 (s, 1H), 6.53 (s, 1H), 3.94 (s, 6H),3.73-3.71 (m, 2H), 2.97-2.96 (m, 2H), 1.90-1.86 (m, 2H). LCMS: (M+H+):m/Z: 341.9

The following compounds were synthesized by the above general procedure:

Compound Number Structure 1HNMR 056

1HNMR (400 MHz, DMSO) 14.4 (brs, 1H), 10.02 (s, 1H), 8.78 (s, 1H), 8.02(s, 1H), 7.23 (s, 1H), 6.47 (brs, 1H), 3.94 (s, 6H), 3.68-3.67 (m, 2H),2.90 (m, 2H), 1.73-1.69 (m, 2H), 1.56-1.52 (m, 2H). MS 355.9 057

1HNMR (400 MHz, DMSO) 14.1 (brs, 1H), 9.57 2H), 6.50-6.41 (m, 2H),3.95-3.92 (m, 6H), 3.67-3.65 (m, 2H), 2.86-2.85 (m, 2H), 1.70-1.60 (m,2H), 1.51- 1.49 (m, 2H), 1.40-1.38 (m, 2H). MS 369.9 005

1HNMR (400 MHz, DMSO) δ 14.39 (bs, 1H), 9.91 (s, 1H), 8.79 (s, 1H), 7.98(s, 1H), 7.22 (s, 1H), 6.52 (s, 2H), 6.44-6.47 (t, 1H), 3.95 (d, 6H),3.86 (m, 2H), 3.69 (t, 2H), 3.53 (t, 2H), 3.02 (m, 2H). MS 372.1

Compound 055 was also synthesized by the above general procedure:

1H NMR 400 MHz, DMSO) 14.42 (brs, 1H), 9.99 (s, 1H), 8.79 (s, 1H), 8.02(s, 1H), 7.23 (s, 1H), 6.61 (s, 1H), 6.53 (s, 1H), 3.94 (s, 6H),3.73-3.71 (m, 2H), 2.97-2.96 (m, 2H), 1.90-1.86 (m, 2H). LCMS 341.9. MW.377.84

Synthesis of Compound 006

Step-1: Synthesis of 4-((3-aminopropyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile (3)

To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile1 (150 mg, 0.60 mmol) in THF (15 mL) was added propane-1,3-diamine 2(223 mg, 3.02 mmol) then stirred the reaction mixture at 50° C. for 20h. The progress of the reaction was monitored by TLC. After completionof the reaction, reaction mixture completely distilled off and absorbedonto celite and reverse phase grace performed using ACN/Water system toafford 4-((3-aminopropyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile(250 mg) as a white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO): δ 8.37 (s, 1H), 8.19 (brs, 1H),7.9 (brs, 1H), 7.78 (s, 1H), 7.22 (s, 1H), 3.99-3.89 (m, 7H), 3.83 (q,2H), 2.87 (t, 2H), 1.99 (t, 2H).

Step-2: Synthesis of tert-butyl(N-(3-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)propyl)sulfamoyl)carbamate(5)

To a stirred solution of4-((3-aminopropyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile 3 (150mg, 0.52 mmol) in DCM (10 mL) was addedN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminiumchloride 4 (193 mg, 0.57 mmol) slowly and then added DIPEA (0.3 ml, 0.78mmol) at same temperature. Then stirred the reaction mixture at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.Reaction mixture was directly absorbed on to silica and converted intoslurry. Crude was purified through combi-flash chromatography by eluting2-3% MeOH in DCM to afford tert-butyl(N-(3-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)propyl)sulfamoyl)carbamate5 (100 mg) as a white solid.

Analytical Data: LCMS: (M+H)⁺: m/Z: 466.2

Step-3: Synthesis of Compound 006

To a stirred solution of tert-butyl(N-(3-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)propyl)sulfamoyl)carbamate5 (95 mg, 0.40 mmol) in dichloromethane (3 ml) was added 4M HCl indioxane (2 mL) at 0° C. then stirred at room temperature for 16 h. Theprogress of the reaction was monitored by TLC. After completion ofreaction, organic solvents completely distilled off under reducedpressure. Crude compound was purified by prep-HPLC to give Compound 006(10 mg) as white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ: 8.33 (s, 1H), 7.79 (t, 1H),7.59 (s, 1H), 7.21 (s, 1H), 6.60 (brs, 2H), 6.53 (brs, 2H), 3.90-3.89(m, 6H), 3.78 (q, 2H), 2.99 (q, 2H), 1.92 (p, 2H).

LCMS: (M+H)⁺: m/Z: 366.2.

Synthesis of Compound 007

Step-1: Synthesis of4-((4-aminobutyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile 3

To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile1 (200 mg, 0.80 mmol) in THF (8 mL) was added butane-1,4-diamine 2 (411mg, 4.03 mmol) then stirred the reaction mixture at 50° C. for 20 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, reaction mixture completely distilled off and absorbed ontocelite and reverse phase grace performed using ACN/Water system toafford 4-((4-aminobutyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile 3(220 mg) as a white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO): δ 8.37 (s, 2H), 8.32 (s, 1H),7.67 (s, 1H), 7.21 (s, 1H), 3.90-3.89 (m, 7H), 3.76 (t, 2H), 2.79 (t,2H), 1.78-1.73 (m, 2H), 1.67-1.64 (m, 2H).

Step-2: Synthesis of tert-butyl(N-(4-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)butyl)sulfamoyl)carbamate5

To a stirred solution of4-((4-aminobutyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile 3 (220 mg,0.73 mmol) in DCM (10 mL) was addedN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminiumchloride 4 (296 mg, 0.88 mmol) slowly and then added DIPEA (0.4 ml, 2.19mmol) at same temperature. Then stirred the reaction mixture at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.Reaction mixture was directly absorbed on to silica and converted intoslurry. Crude was purified through combi-flash chromatography by eluting2-3% MeOH in DCM to afford tert-butyl(N-(4-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)butyl)sulfamoyl)carbamate5 (100 mg) as a white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO): δ 8.46-8.44 (m, 1H), 8.31 (s,1H), 7.82 (t, 1H), 7.60-7.57 (m, 2H), 7.20 (s, 1H), 3.90-3.89 (m, 6H),3.72 (q, 2H), 2.92-2.91 (m, 2H), 1.73-1.70 (m, 2H), 1.58-1.54 (m, 2H).

LCMS: (M+H)⁺: m/Z: 480

Step-3: Synthesis of Compound 007

To a stirred solution of tert-butyl(N-(4-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)butyl)sulfamoyl)carbamate5 (100 mg, 0.20 mmol) in dichloromethane (3 ml) was added 4M HCl indioxane (1 mL) at 0° C. then stirred at room temperature for 16 h. Theprogress of the reaction was monitored by TLC. After completion ofreaction, organic solvents completely distilled off under reducedpressure. Crude compound was purified by prep-HPLC to give Compound 007(10 mg) as white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ: 8.35-8.31 (m, 2H), 7.86 (t,1H), 7.60 (s, 1H), 7.20 (s, 1H), 6.50 (t, 2H), 6.46 (s, 1H), 3.90-3.89(m, 6H), 3.73 (q, 2H), 2.90 (q, 2H), 1.75-1.71 (m, 2H), 1.61-1.53 (m,2H).

LCMS: (M+H)⁺: m/Z: 380.24.

Synthetic Scheme of Compound 008

Step-1: Synthesis of4-((5-aminopentyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile 3

To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile1 (200 mg, 0.80 mmol) in THF (8 mL) was added butane-1,4-diamine 2(411.2 mg, 4.03 mmol) then stirred the reaction mixture at 50° C. for 20h. The progress of the reaction was monitored by TLC. After completionof the reaction, reaction mixture completely distilled off and absorbedonto celite and reverse phase grace performed using ACN/Water system toafford 4-((5-aminopentyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile 3(200 mg) as a white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO): δ 8.48 (s, 1H), 8.30 (s, 1H),7.98 (brs, 1H), 7.66 (s, 1H), 7.19 (s, 1H), 3.90-3.89 (m, 6H), 3.72-3.71(m, 2H), 2.60-2.56 (m, 2H), 1.73-1.66 (m, 2H), 1.48-1.21 (m, 4H).

LCMS: (M+H)⁺: m/Z: 315.23

Step-2: Synthesis of tert-butyl(N-(5-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)pentyl)sulfamoyl)carbamate5

To a stirred solution of4-((5-aminopentyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile 3 (220mg, 0.63 mmol) in DCM (10 mL) was addedN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminiumchloride 4 (266 mg, 0.76 mmol) slowly and then added DIPEA (0.17 ml,0.95 mmol) at same temperature. Then stirred the reaction mixture atroom temperature for 16 h. The progress of the reaction was monitored byTLC. Reaction mixture was directly absorbed on to silica and convertedinto slurry. Crude was purified through combi-flash chromatography byeluting 2-3% MeOH in DCM to afford tert-butyl(N-(5-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)pentyl)sulfamoyl)carbamate5 (130 mg) as a white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO): δ 10.75 (s, 1 h), 8.31 (s, 1H),7.82 (t, 1H), 7.60 (s, 1H), 7.51 (brs, 1H), 7.20 (s, 1H), 3.90-3.89 (m,6H), 3.71 (q, 2H), 2.87 (q, 2H), 1.72-1.64 (m, 2H), 1.58-1.47 (m, 2H),1.22 (m, 2H).

LCMS: (M+H)⁺: m/Z: 494.2

Step-3: Synthesis of Compound 008

To a stirred solution of tert-butyl(N-(5-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)pentyl)sulfamoyl)carbamate5 (130 mg, 0.20 mmol) in dichloromethane (4 ml) was added 4M HCl indioxane (1.5 mL) at 0° C. then stirred at room temperature for 16 h. Theprogress of the reaction was monitored by TLC. After completion ofreaction, organic solvents completely distilled off under reducedpressure. Crude compound was purified by prep-HPLC to give Compound 008(10 mg) as white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ: 8.31 (s, 1H), 8.12 (s, 1H),7.84 (t, 1H), 7.60 (s, 1H), 7.20 (s, 1H), 6.45-6.44 (m, 3H), 3.90-3.89(m, 6H), 3.72 (q, 2H), 2.86 (q, 2H), 3.01 (t, 2H), 1.73-1.65 (m, 2H),1.55-1.48 (m, 2H), 1.43-1.40 (m, 2H).

LCMS: (M+H)⁺: m/Z: 394.2.

Synthetic Scheme for Compounds 009 and 010

Synthesis ofN1-(7-(benzyloxy)-6-methoxyquinazolin-4-yl)butane-1,4-diamine (3)

To a stirred solution of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline (1)(1 g, 3.33 mmol) in tetrahydrofuran (20 mL) was added butane-1,4-diamine2 (1.5 g, 16.66 mmol) at RT and stirred the reaction mixture at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, organic solvents completely distilledoff under reduced pressure to afford crude compound. Crude compound waspurified through Grace reverse phase chromatography by eluting 40%acetonitrile in water to afford pure compound ofN1-(7-(benzyloxy)-6-methoxyquinazolin-4-yl) butane-1,4-diamine (3) (1 g,0.284 mmol, 85% yield) as a light brown thick liquid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 7.95-7.98 (m,1H), 7.59 (s, 1H), 7.32-7.48 (m, 5H), 7.15 (s, 1H), 5.22 (s, 2H), 3.87(s, 3H), 3.47-3.51 (m, 2H), 2.56-2.59 (m, 2H), 1.62-1.66 (m, 2H),1.41-1.44 (m, 2H).

LCMS: (M+H⁺): m/z: 353.2

Synthesis of tert-butyl(N-(4-((7-(benzyloxy)-6-methoxyquinazolin-4-yl)amino)butyl)sulfamoyl)carbamate(Int-5)

To a stirred solution ofN1-(7-(benzyloxy)-6-methoxyquinazolin-4-yl)butane-1,4-diamine (3) (1.0g, 2.84 mmol) in dichloromethane (20 mL) was added diisopropylethylamine(1.5 mL, 8.52 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium4 (957 mg, 2.84 mmol) at RT, then stirred at room temperature for 16 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified combiflash column chromatography by eluting 10% MeOH in DCM to afford (Int-5)(1.1 g, 2.07 mmol, 73% yield) as a pale yellow solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 10.83 (br s, 1H), 8.3 (s, 1H),7.93 (brs, 1H), 7.59-7.561 (m, 2H), 7.46-7.61 (d, 2H), 7.32-7.42 (m,3H), 7.16 (s, 1H), 5.226 (s, 2H), 4.03 (s, 1H), 3.88 (s, 3H), 3.46-3.50(m, 2H), 2.89-2.93 (m, 2H), 1.62-1.66 (m, 2H), 1.52-1.54 (m, 2H), 1.38(s, 9H).

LCMS: (M+H)⁺: m/Z: 532.2

Synthesis of tert-butyl(N-(4-((7-hydroxy-6-methoxyquinazolin-4-yl)amino)butyl)sulfamoyl)carbamate(Int-6)

To a stirred solution of tert-butyl(N-(4-((7-(benzyloxy)-6-methoxyquinazolin-4-yl)amino)butyl)sulfamoyl)carbamate(5) (1 g, 1.88 mmol) in methanol (15 mL) and EtOAc (2.5 mL) was added10% Pd/C (100 mg) and stirred the reaction mixture under balloonhydrogen atmosphere at room temperature for 6 h. The progress of thereaction was monitored by TLC. After completion of the reaction,reaction mixture filtered through celite and washed the celite bed with5% methanol in dichloromethane (100 mL). Filtrate was concentrated underreduced pressure to afford tert-butyl(N-(4-((7-hydroxy-6-methoxyquinazolin-4-yl)amino)butyl)sulfamoyl)carbamate(6) (800 mg, 1.81 mmol, 96% yield) as a pale yellow solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 10.13 (br s, 1H), 8.24 (s,1H), 7.83 (brs, 1H), 7.54-7.57 (m, 2H), 6.92 (s, 1H), 3.87 (s, 3H),3.45-3.50 (m, 2H), 2.88-2.93 (m, 2H), 1.59-1.65 (m, 2H), 1.50-1.53 (m,2H), 1.38 (s, 9H).

LCMS: (M+H⁺): m/Z: 442.2

Preparation of Compound 009

To a stirred solution of Int-6 (100 mg, 0.226 mmol) in 1,4-dioxane (1.0mL) was added 4M HCl in dioxane (2.0 mL) at RT. Reaction mixture wasstirred at RT for 6 h. The progress of the reaction was monitored byTLC. After completion of the reaction, organic solvents completelydistilled off under reduced pressure to afford crude compound. Crudecompound was purified through prep HPLC method to afford pure compoundof Compound 009 (50 mg, 0.146 mmol, 64% yield) as an Off-white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO-d₆) δ 14.27 (brs, 1H), 11.41 (s,1H), 9.80 (s, 1H), 8.70 (s, 1H), 7.94 (s, 1H), 7.19 (s, 1H), 6.47-6.51(m, 3H), 3.93 (s, 3H), 3.61-3.68 (m, 2H), 2.87-2.92 (m, 2H), 1.66-1.71(m, 2H), 1.49-1.57 (m, 2H), 1.23-1.28 (m, 2H).

LCMS: (M+H)⁺: m/Z: 342.1

Preparation of Compound 010

To a stirred solution of Int-5 (100 mg, 0.188 mmol) in 1,4-dioxane (1.0mL) was added 4M HCl in dioxane (2.0 mL) at RT. Reaction mixture wasstirred at RT for 6 h. The progress of the reaction was monitored byTLC. After completion of the reaction, organic solvents completelydistilled off under reduced pressure to afford crude compound. Crudecompound was purified through prep HPLC method to afford pure compoundof Int-5 (50 mg, 1.16 mmol, 61% yield) as an Off-white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 8.3 (s, 1H), 8.14 (s, 2H),7.92 (m, 1H), 7.6 (s, 1H), 7.47-7.49 (d, 2H), 7.39-7.41 (t, 2H),7.35-7.37 (m, 1H), 7.17 (s, 1H), 6.45 (s, 1H), 5.23 (s, 2H), 3.89 (s,3H), 3.50-3.51 (m, 2H), 2.89-2.94 (m, 2H), 1.66-1.70 (m, 2H), 1.54-1.56(m, 2H).

LCMS: (M+H)⁺: m/Z: 432.2

Synthetic Scheme for Compound 011

4-((4-((N-(tert-butoxycarbonyl)sulfamoyl)amino)butyl)amino)-6-methoxyquinazolin-7-yltrifluoromethanesulfonate (Int-5)

To a stirred solution of Int-6 (500 mg, 1.13 mmol) in dichloromethane(20 mL) were added triethylamine (0.475 mL, 3.39 mmol) and1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide2 (445 mg, 1.24 mmol) at 0° C. then stirred at room temperature 4 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, organic solvents completely distilled off under reducedpressure and water (200 mL) was added to the crude and partitioned withdichloromethane (2×200 mL). Combined organic layers were washed withbrine solution (200 mL), dried over sodium sulfate and concentratedunder reduced pressure. Crude was purified by combi-flash chromatographyby eluting 70% ethyl acetate in pet ether to afford4-((4-((N-(tert-butoxycarbonyl)sulfamoyl)amino)butyl)amino)-6-methoxyquinazolin-7-yltrifluoromethanesulfonate Int-5 (450 mg, 0.785 mmol, 69% yield over twosteps) as a pale yellow solid.

LCMS: (M+H⁺): m/Z: 574.1

Preparation of Compound 011

In a sealed tube, to the stirred solution of4-((4-((N-(tert-butoxycarbonyl)sulfamoyl)amino)butyl)amino)-6-methoxyquinazolin-7-yltrifluoromethanesulfonate Int-5 (50 mg, 0.349 mmol) in dioxane (2 mL)and water (05 mL) were added tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(33 mg, 0.113 mmol) and cesium fluoride (40 mg, 0.26 mmol) was thendegassed the reaction mixture for 30 minutes. Thentetrakis(triphenylphosphine)palladium(0) (100 mg, 0.0087 mmol) was addedagain degassed for 5 minutes and stirred the reaction mixture at 100° C.for 5 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, reaction mixture was poured into water (100mL) and filtered through celite. Washed the celite bed with 10% methanolin dichloromethane (100 mL) and separated the two layers. Organic layerwashed with brine solution (200 mL), dried over sodium sulfate andconcentrated under reduced pressure. Crude was purified prep HPLC methodto afford (Compound 011) (10 mg, 0.127 mmol, 29%) as a Off-white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 12.96 (brs, 1H), 8.39 (s, 1H),8.23 (brs, 1H), 8.13 (s, 2H), 7.74 (s, 2H), 6.88 (d, 1H), 6.495 (t, 1H),6.46 (s, 2H), 4.0 (s, 3H), 3.53-3.58 (q, 2H), 2.90-2.95 (q, 2H),1.66-1.72 (m, 2H), 1.55-1.59 (m, 2H).

LCMS: (M+H⁺): m/Z: 392.1

Example 3: N-(4-((6, 7-dimethoxyquinazolin-4-yl) thio) butyl) sulfamidehydrochloride Step 1: Synthesis of 6, 7-dimethoxyquinazoline-4-thiol

To a stirred solution of 4-chloro-6, 7-dimethoxyquinazoline (500 mg, 2.2mmol) in ethanol (5 ml) was added thio urea (338 mg, 4.44 mmol) at RTand stirred the reaction mixture at reflux for 4 h. The progress of thereaction was monitored by TLC. After completion of the reaction,reaction mixture was allowed to settle at RT. Solid formed was collectedby filtration which is the desired compound 6,7-dimethoxyquinazoline-4-thiol (400 mg, 1.801 mmol, 80% yield) as alight brown solid. 1H NMR (400 MHz, DMSO) δ 13.67 (s, 1H), 8.09-8.10 (s,1H), 7.90 (s, 1H), 7.16 (s, 1H), 3.93 (s, 3H), 3.89 (s, 3H). LCMS:(M+H)+: m/Z: 222.9

Step 2: Synthesis of 2-(4-((6, 7-dimethoxyquinazolin-4-yl) thio) butyl)isoindoline-1, 3-dione

To a stirred solution of 6,7-dimethoxyquinazoline-4-thiol (1 g, 4.5mmol) in DMF (10 ml) were added potassium carbonate (684 mg, 4.95 mmol)and 2-(4-bromobutyl)isoindoline-1,3-dione (1.27 g, 4.5 mmol) thenstirred at 90° C. for 6 h. The progress of the reaction was monitored byTLC. After completion of the reaction, reaction mixture was poured onwater and extracted with ethyl acetate. Organic layer was separated waswashed with water and was concentrated under reduced pressure to affordthe pure compound of 2-(4-((6, 7-dimethoxyquinazolin-4-yl) thio) butyl)isoindoline-1, 3-dione (800 mg, 1.891 mmol, 42% yield) as a light brownsolid. 1H NMR (400 MHz, DMSO) δ 8.75 (s, 1H), 7.81-7.82 (m, 4H), 7.26(s, 1H), 7.13 (s, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.61 (t, 2H),3.30-3.36 (m, 2H), 1.75 (m, 4H). LCMS: (M+H)+: m/Z: 424.2.

The following compound was synthesized by the above procedure

Structure 1HNMR

(400 MHz, DMSO) δ 8.79 (s, 1H), 7.83- 7.78 (m, 4H), 7.28 (s, 1H), 7.13(s, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.58-3.55 (t, 2H), 3.37-3.30 (t,2H), 1.75-1.70 (m, 2H), 1.68-1.61 (m, 2H), 1.47-1.43 (m, 2H). MS 437.9

Step 3: Synthesis of 4-((6,7-dimethoxyquinazolin-4-yl)thio)butan-1-amine

To a stirred solution of2-(4-((6,7-dimethoxyquinazolin-4-yl)thio)butyl)isoindoline-1,3-dione(1.1 g, 2.60 mmol) in ethanol (30 ml) were added 90% of hydrazinehydrate (0.163 mL, 5.2 mmol) at RT, then reaction mixture was stirred atreflux for 2 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, reaction mixture was cooled to RT,precipitate formed. Solid was collected through filtration affording4-((6, 7-dimethoxyquinazolin-4-yl) thio) butan-1-amine (700 mg, 2.389mmol, 92% yield) as a light brown solid. 1H NMR (400 MHz, DMSO) δ 8.81(s, 1H), 7.29 (s, 1H), 7.16 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.35(t, 2H), 2.67 (t, 2H), 1.77-1.71 (m, 2H), 1.62-1.56 (m, 2H). LCMS:(M+H)+: m/Z: 294.1

The following compound was synthesized by the above procedure

Structure 1HNMR

MS 308.1

Step-4: Tert-butyl (N-(4-((6, 7-dimethoxyquinazolin-4-yl) thio) butyl)sulfamoyl) carbamate

To a stirred solution of4-((6,7-dimethoxyquinazolin-4-yl)thio)butan-1-amine 5 (550 mg, 1.87mmol) in dichloromethane (20 ml) were added diisopropylethylamine (1.6mL, 9.38 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminiumchloride 4 (337 mg, 1.87 mmol) at RT, then stirred at room temperaturefor 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, organic solvents completely distilled offunder reduced pressure to afford crude compound. Crude compound waspurified using combi flash column chromatography by eluting 60% ethylacetate in pet-ether to afforded tert-butyl (N-(4-((6,7-dimethoxyquinazolin-4-yl) thio) butyl) sulfamoyl) carbamate 6 (150 mg,0.317 mmol, 17% yield) as a white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ: 10.79 (s, H), 8.82 (s, 1H),7.62-7.59 (t, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 3.95 (s, 3H), 3.93 (s,3H), 3.34 (t, 2H), 2.94-2.90 (m, 2H), 1.77-1.70 (m, 2H), 1.64-1.59 (m,2H), 1.39 (s, 9H).

LCMS: (M+H)+: m/Z: 473.2

Structure 1HNMR

1H NMR (400 MHz, DMSO) δ 10.72 (bs, 1H), 8.81 (s, 1H), 7.50 (bs, 1H),7.29 (bs, 1H), 7.16 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.35 (t, 2H),2.86 (t, 2H), 1.75 (t, 2H), 1.50-1.44 (m, 4H), 1.39 (s, 9H). MS 487.2

Step-5: N-(4-((6, 7-dimethoxyquinazolin-4-yl) thio) butyl) sulfamidehydrochloride

To a stirred solution of tert-butyl(N-(4-((6,7-dimethoxyquinazolin-4-yl)thio)butyl)sulfamoyl)carbamate (6)(100 mg, 0.211 mmol) in 1,4-dioxane (1.0 ml) was added 4M HCl in dioxane(2 mL) at RT. Reaction mixture was stirred at RT for 16 h. The progressof the reaction was monitored by TLC. After completion of the reaction,organic solvents completely distilled off under reduced pressure toafford crude compound. Crude compound was purified through preparativeHPLC method to afford pure compound of N-(4-((6,7-dimethoxyquinazolin-4-yl) thio) butyl) sulfamide hydrochloride (30 mg,0.08 mmol, 25% yield) as an off white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 7.30 (s, 1H),7.18 (s, 1H), 6.53-6.47 (m, 3H), 3.95 (s, 3H), 3.93 (s, 3H), 3.37-3.32(m, 2H), 2.93-2.88 (m, 2H), 1.77-1.72 (m, 2H), 1.66-1.60 (m, 2H).

LCMS: (M+H)+: m/Z: 373.23

The following compound was synthesized by the above general procedure

Compound Number Structure 1HNMR 012

1HNMR (400 MHz, DMSO) δ 8.82 (s, 1H), 7.30 (s, 1H), 7.18 (s, 1H), 6.45(s, 3H), 3.95 (s, 3H), 3.93 (s, 3H), 3.34 (t, 2H), 2.86 (d, 2H), 1.72(t, 2H), 1.48 (brs, 4H). MS 387.1

Compound 058 was also synthesized by the above general procedure.

1H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 7.30 (s, 1H), 7.18 (s, 1H),6.53-6.47 (m, 3H), 3.95 (s, 3H), 3.93 (s, 3H), 3.37-3.32 (m, 2H),2.93-2.88 (m, 2H), 1.77-1.72 (m, 2H), 1.66-1.60 (m, 2H). LCMS 373.23.MW. 408.92

Compound 059 was also synthesized by the above general procedure.

1H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 7.30 (s, 1H), 7.18 (s, 1H), 6.45(s, 3H), 3.95 (s, 3H), 3.93 (s, 3H), 3.34 (t, 2H), 2.86 (d, 2H), 1.72(t, 2H), 1.48 (brs, 4H). LCMS 387.1. MW. 422.94

Synthetic Scheme of Compounds 013 and 014

Step-1: Synthesis of 4-mercapto-6,7-dimethoxyquinoline-3-carbonitrile 2

To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile1 (2000 mg, 8.06 mmol) in Ethanol (30 mL) was added thiourea (920 mg,12.08 mmol) then refluxed for 6 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, reaction mixturecompletely distilled off and absorbed onto silica and grace columnchromatography was performed using methanol/DCM to afford4-mercapto-6,7-dimethoxyquinoline-3-carbonitrile 2 (1300 mg) as palepink solid.

Analytical Data: ¹H NMR (400 MHz, DMSO): δ 13.51 (brs, 1H), 8.57 (s,1H), 8.05 (s, 1H), 7.09 (s, 1H), 3.91-3.88 (m, 6H).

LCMS: (M+H)⁺: m/Z: 247.1

Step-2: Synthesis of4-((4-(1,3-dioxoisoindolin-2-yl)butyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile4

To a stirred solution of4-mercapto-6,7-dimethoxyquinoline-3-carbonitrile 2 (450 mg, 1.8 mmol) inDMF (10 mL) was added 2-(4-bromobutyl)isoindoline-1,3-dione 3 (513 mg,1.8 mmol) slowly and then K₂CO₃ (277 mg, 2.01 mmol) at RT. Afteraddition, the reaction mixture heated to 90° C. for 6 h. The progress ofthe reaction was monitored by TLC. After completion of reaction,reaction mixture was directly poured on to ice cold water and stirred.Solid precipitated out was filtered and washed again with water anddried without necessity of any further purification to afford4-((4-(1,3-dioxoisoindolin-2-yl)butyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile4 (600 mg) as a light brown solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ: 8.86 (s, 1H), 7.81-7.75 (m,4H), 7.66 (s, 1H), 7.41 (s, 1H), 3.97-3.96 (m, 6H), 3.49 (t, 2H), 3.21(t, 2H), 1.72-1.65 (m, 2H), 1.50-1.43 (m, 2H).

LCMS: (M+H)⁺: m/Z: 448.26

Step-3: Synthesis of4-((4-aminobutyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 5

To a stirred solution of4-((4-(1,3-dioxoisoindolin-2-yl)butyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile4 (550 mg, 1.2 mmol) in EtOH (10 mL) was added Hydrazine hydrate (0.19ml, 3.7 mmol) was added and then refluxed for 2 h. The progress of thereaction was monitored by TLC. After completion, reaction mixture wasdirectly absorbed on to celite and converted into slurry. Crude waspurified through reverse-phase grace column chromatography by eluting40% ACN/water system to afford4-((4-aminobutyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 5 (80 mg)as a pale yellow liquid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ: 8.91 (s, 1H), 7.71 (s, 1H),7.50 (s, 1H), 3.99-3.96 (m, 6H), 3.20-3.15 (m, 2H), 2.45-2.44 (m, 2H),1.53-1.41 (m, 4H).

LCMS: (M+H)⁺: m/Z: 318.2

Step-4: Synthesis of tert-butyl(N-(4-((3-cyano-6,7-dimethoxyquinolin-4-yl)thio)butyl)sulfamoyl)carbamate7

To a stirred solution of4-((4-aminobutyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 5 (80 mg,0.25 mmol) in DCM (10 mL) was addedN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminiumchloride 4 (85 mg, 0.25 mmol) slowly and then added DIPEA (0.07 ml,0.375 mmol) at same temperature. Then stirred the reaction mixture atroom temperature for 16 h. The progress of the reaction was monitored byTLC. Reaction mixture was directly absorbed on to silica and convertedinto slurry. Crude was purified through combi-flash chromatography byeluting 70% EtOAc in Hexane to afford tert-butyl(N-(4-((3-cyano-6,7-dimethoxyquinolin-4-yl)thio)butyl)sulfamoyl)carbamate5 (90 mg) as a white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ: 10.73 (s, 1H), 8.92 (s, 1H),7.71 (s, 1H), 7.55-7.50 (m, 2H), 3.99-3.98 (m, 6H), 3.19-3.17 (m, 2H),2.82-2.81 (m, 2H), 1.53-1.52 (m, 4H), 1.37 (s, 9H).

LCMS: (M+H)⁺: m/Z: 497.2

Step-5: Synthesis of Compound 013

To a stirred solution of tert-butyl(1V-(4-((3-cyano-6,7-dimethoxyquinolin-4-yl)thio)butyl)sulfamoyl)carbamate7 (90 mg, 0.18 mmol) in dichloromethane (3 ml) was added 4M HCl indioxane (1 mL) at 0° C. then stirred at room temperature for 16 h. Theprogress of the reaction was monitored by TLC. After completion ofreaction, organic solvents completely distilled off under reducedpressure. Crude compound was purified by prep-HPLC to give Compound 013(25 mg) as off-white fluffy solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ: 8.92 (s, 1H), 7.72 (s, 1H),7.51 (s, 1H), 6.45-6.42 (m, 3H), 6.45 (t, 1H) 3.99-3.98 (m, 6H),3.21-3.17 (m, 2H), 2.82-2.77 (m, 2H), 1.55-1.53 (m, 4H).

LCMS: (M+H)⁺: m/Z: 397.1.

Step-6: Synthesis of4-((5-(1,3-dioxoisoindolin-2-yl)pentyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile9

To a stirred solution of4-mercapto-6,7-dimethoxyquinoline-3-carbonitrile 2 (450 mg, 1.8 mmol) inDMF (10 mL) was added 2-(5-bromopentyl)isoindoline-1,3-dione 8 (540 mg,1.8 mmol) slowly and then K₂CO₃ (273 mg, 1.98 mmol) at RT. Afteraddition, the reaction mixture heated to 90° C. for 6 h. The progress ofthe reaction was monitored by TLC. After completion of reaction,reaction mixture was directly poured on to ice cold water and stirred.Solid precipitated out was filtered and washed again with water anddried without necessity of any further purification to afford4-((5-(1,3-dioxoisoindolin-2-yl)pentyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile9 (600 mg) as a light brown solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ: 8.89 (s, 1H), 7.81-7.75 (m,4H), 7.69 (s, 1H), 7.48 (s, 1H), 3.98-3.96 (m, 6H), 3.49 (t, 2H), 3.17(t, 2H), 1.56-1.46 (m, 4H), 1.40-1.36 (m, 2H).

LCMS: (M+H)⁺: m/Z: 462.1

Step-7: Synthesis of4-((5-aminopentyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 10

To a stirred solution of4-((5-(1,3-dioxoisoindolin-2-yl)pentyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile9 (600 mg, 1.3 mmol) in DCM:MeOH (1:1) (10 mL) was added 1,2Diethylamine (0.43 ml, 6.5 mmol) then heated at 40° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion,reaction mixture was directly absorbed on to celite and converted intoslurry. Crude was purified through reverse-phase grace columnchromatography by eluting 30-40% ACN/water system to afford4-((5-aminopentyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 10 (200mg) as a pale yellow liquid.

Analytical Data: LCMS: (M+H)⁺: m/Z: 332.2

Step-8: Synthesis of tert-butyl(N-(5-((3-cyano-6,7-dimethoxyquinolin-4-yl)thio)pentyl)sulfamoyl)carbamate11

To a stirred solution of4-((5-aminopentyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 10 (200mg, 0.60 mmol) in DCM (10 mL) was addedN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminiumchloride 4 (338 mg, 0.6 mmol) slowly and then added DIPEA (0.16 ml, 0.9mmol) at same temperature. Then stirred the reaction mixture at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.Reaction mixture was directly absorbed on to silica and converted intoslurry. Crude was purified through combi-flash chromatography by eluting70-80% EtOAc in Hexane to afford tert-butyl(N-(5-((3-cyano-6,7-dimethoxyquinolin-4-yl)thio)pentyl)sulfamoyl)carbamate11 (90 mg) as a white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ: 10.73 (s, 1H), 8.92 (s, 1H),7.71 (s, 1H), 7.55-7.50 (m, 2H), 4.00-3.98 (m, 6H), 3.18-3.14 (m, 2H),2.80-2.79 (m, 2H), 1.45-1.41 (m, 2H), 1.37 (m, 13H).

LCMS: (M+H)⁺: m/Z: 511.2

Step-9: Synthesis of Compound 014

To a stirred solution of tert-butyl(N-(5-((3-cyano-6,7-dimethoxyquinolin-4-yl)thio)pentyl)sulfamoyl)carbamate11 (90 mg, 0.176 mmol) in dichloromethane (2 ml) was added 4M HCl indioxane (1 mL) at 0° C. then stirred at room temperature for 16 h. Theprogress of the reaction was monitored by TLC. After completion ofreaction, organic solvents completely distilled off under reducedpressure. Crude compound was purified by prep-HPLC to give Compound 014(29 mg) as off-white fluffy solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ: 8.93 (s, 1H), 7.73 (s, 1H),7.51 (s, 1H), 6.41-6.39 (m, 3H), 4.09-3.99 (m, 6H), 3.19 (t, 2H),2.80-2.78 (m, 2H), 1.51-1.49 (m, 2H), 1.48-1.40 (m, 4H).

LCMS: (M+H)⁺: m/Z: 411.1.

Example 4: N-(5-((6, 7-dimethoxyquinazolin-4-yl) (methyl) amino) pentyl)sulfamide Step-1: Tert-butyl (5-(1, 3-dioxoisoindolin-2-yl) pentyl)carbamate

To a stirred solution of tert-butyl (5-aminopentyl) carbamate 1 (500 mg,2.47 mmol) in toluene (10 mL) was added isobenzofuran-1, 3-dione 2 (366mg, 2.47 mmol) then stirred the reaction mixture at reflux for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, reaction mixture completely distilled off under reducedpressure to afford crude compound. Crude was purified throughcombi-flash column chromatography by eluting 20% ethyl acetate in petether to afford tert-butyl (5-(1, 3-dioxoisoindolin-2-yl) pentyl)carbamate (500 mg, 1.506 mmol, 61% yield) as a white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 7.86-7.80 (m, 4H), 6.74 (t,1H), 3.56-3.52 (t, 2H), 2.88-2.83 (m, 2H), 1.58-1.54 (m, 2H), 1.38-1.32(m, 11H), 1.23-1.20 (m, 2H).

LCMS: (M+Na)+: m/Z: 355.41

Step-2: Tert-butyl (5-(1, 3-dioxoisoindolin-2-yl) pentyl) (methyl)carbamate

To a stirred solution of tert-butyl(5-(1,3-dioxoisoindolin-2-yl)pentyl)carbamate 3 (2 g, 6.024 mmol) inN,N′-dimethylformamide (20 mL) was added 60% NaH (723 mg, 30.12 mmol)slowly at 0° C. and then added methyl iodide (8.5 g, 60.24 mmol) at sametemperature. Then stirred the reaction mixture at room temperature for16 h. The progress of the reaction was monitored by TLC. Reactionmixture was poured into ice cold water (500 mL) and extracted with ethylacetate (2×400 mL). Combined organic layers were washed with brinesolution (400 mL), dried over sodium sulfate and concentrated underreduced pressure. Crude was purified through combi-flash chromatographyby eluting 20% ethyl acetate in pet ether to afford mixture oftert-butyl (5-(1, 3-dioxoisoindolin-2-yl) pentyl) (methyl) carbamate 4(1.44 g, 4.161 mmol, 69% yield) as a white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 7.86-7.80 (m, 4H), 3.57-3.54(t, 2H), 3.12-3.08 (t, 2H), 2.71 (s, 3H), 1.63-1.56 (m, 2H), 1.48-1.43(m, 2H), 1.32 (s, 9H), 1.20-1.17 (m, 2H).

LCMS: (M−Boc)+: m/Z: 247.2

Step-3: 2-(5-(methyl amino) pentyl) isoindoline-1,3-dione hydrochloride

To a stirred solution of tert-butyl4-(2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)ethyl)-3,4-dihydroquinoline-1(2H)-carboxylate4 (1.8 g, 5.202 mmol) in dichloromethane (15 ml) was added 4M HCl indioxane (6.75 mL) at 0° C. then stirred at room temperature for 2 h. Theprogress of the reaction was monitored by TLC. After completion ofreaction, organic solvents completely distilled off under reducedpressure. Crude compound was purified by trituration with diethyl ether(100 mL) to afford 2-(5-(methyl amino) pentyl) isoindoline-1, 3-dionehydrochloride 5 (1.3 g, 4.609 mmol, 89% yield) as a white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.32 (brs, 2H), 7.87-7.82 (m,4H), 3.58-3.55 (t, 2H), 2.83 (m, 2H), 1.63-1.53 (m, 4H), 1.33-1.28 (m,2H).

LCMS: (M+H)+: m/Z: 247.2

Step-4: 2-(5-((6, 7-dimethoxyquinazolin-4-yl) (methyl) amino) pentyl)isoindoline-1, 3-dione

To a stirred solution of 2-(5-(methyl amino) pentyl) isoindoline-1,3-dione hydrochloride 5 (1.2 g, 4.25 mmol) in acetonitrile (15 ml) wereadded potassium carbonate (1.76 g, 13.5 mmol) and 4-chloro-6,7-dimethoxyquinazoline 6 (953 mg, 4.25 mmol) then stirred at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, added water (200 mL) and extractedwith ethyl acetate (2×150 mL). Combined organic layers were washed withbrine solution (100 mL), dried over sodium sulfate and concentratedunder reduced pressure. Crude was purified through combi-flash columnchromatography by eluting 40% ethyl acetate in hexane to afford2-(5-((6, 7-dimethoxyquinazolin-4-yl) (methyl) amino) pentyl)isoindoline-1, 3-dione 7 (650 mg, 1.497 mmol, 44% yield) as a whitesolid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 7.84-7.79 (m,4H), 7.21 (s, 1H), 7.11 (s, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 3.60-3.54(m, 2H), 3.21 (s, 3H), 1.78-1.75 (m, 2H), 1.65-1.59 (m, 2H), 1.34-1.28(m, 2H).

LCMS: (M+H)+: m/Z: 435.2

Step-5: N1-(6, 7-dimethoxyquinazolin-4-yl)-N1-methylpentane-1, 5-diamine

To a stirred solution of2-(5-((6,7-dimethoxyquinazolin-4-yl)(methyl)amino)pentyl)isoindoline-1,3-dione7 (545 mg, 1.126 mmol) in ethanol (15 ml) was added hydrazine hydrate(0.18 mL, 3.378 mmol) then stirred the reaction mixture at 80° C. for 2h. The progress of the reaction was monitored by TLC. After completionof reaction, precipitated solid was filtered off, washed the residuewith ethanol (20 mL) and concentrated the filtrate to afford crudecompound. Crude compound was purified through Grace reverse phase methodby eluting 14% acetonitrile in 0.1% formic acid in water to affordN1-(6, 7-dimethoxyquinazolin-4-yl)-N1-methylpentane-1, 5-diamine 8 (330mg, 1.085 mmol, 86% yield) as a colorless gummy liquid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 7.25 (s, 1H),7.14 (s, 1H), 3.90 (s, 3H), 3.90 (s, 3H), 3.60-3.56 (t, 2H), 3.22-3.21(s, 3H), 1.76-1.72 (m, 2H), 1.38-1.30 (m, 4H).

LCMS: (M+H)+: m/Z: 305.2

Step-6: Tert-butyl (N-(5-((6, 7-dimethoxyquinazolin-4-yl) (methyl)amino) pentyl) sulfamoyl) carbamate

To a stirred solution ofN1-(6,7-dimethoxyquinazolin-4-yl)-N1-methylpentane-1,5-diamine 8 (360mg, 1.2 mmol) in dichloromethane (10 ml) were addeddiisopropylethylamine (0.3 mL, 1.81 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminiumchloride 9 (491 mg, 1.45 mmol) at 0° C. then stirred at room temperaturefor 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, organic solvents completely distilled offunder reduced pressure to afford crude compound. Crude was purifiedthrough 60-120 silica gel column chromatography by eluting 2% methanolin dichloromethane to afford tert-butyl (N-(5-((6,7-dimethoxyquinazolin-4-yl) (methyl) amino) pentyl) sulfamoyl) carbamate10 (200 mg, 0.414 mmol, 35% yield) as a brown solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 11.0-10.0 (brs, 1H), 8.38 (s,1H), 7.25 (s, 1H), 7.22 (m, 1H), 7.14 (s, 1H), 3.90 (s, 3H), 3.87 (s,3H), 3.59-3.55 (t, 2H), 3.22-3.21 (s, 3H), 1.75-1.71 (m, 2H), 1.50-1.45(m, 2H), 1.38 (s, 9H), 1.31-1.24 (m, 1H). LCMS: (M+H)+: m/Z: 484.2

Step 7: N-(5-((6, 7-dimethoxyquinazolin-4-yl) (methyl) amino) pentyl)sulfamide (Compound 061)

To a stirred solution of tert-butyl(N-(5-((6,7-dimethoxyquinazolin-4-yl)(methyl)amino)pentyl)sulfamoyl)carbamate10 (200 mg, 0.414 mmol) in dichloromethane (6 ml) was added 4M HCl indioxane (4 mL) at 0° C. then stirred at room temperature for 3 h. Theprogress of the reaction was monitored by TLC. After completion, organicsolvents completely distilled off under reduced pressure to afford crudecompound. Crude was purified through prep HPLC method to affordN-(5-((6, 7-dimethoxyquinazolin-4-yl) (methyl) amino) pentyl) sulfamide(90 mg, 0.235 mmol, 57% yield) (Compound 061) as an off white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.39 (s, 1H), 8.14 (s, 1H),7.26 (s, 1H), 7.14 (s, 1H), 6.44 (m, 3H), 3.90 (s, 3H), 3.88 (s, 3H),3.60-3.56 (t, 2H), 2.88-2.83 (m, 2H), 1.77-1.71 (m, 2H), 1.52-1.46 (m,2H), 1.37-1.31 (m, 2H). LCMS: (M+H)+: m/Z: 384.2

Example 5: 4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamidehydrochloride Salt (Compound 015) Step-1: Tert-butyl 4-(6,7-dimethoxyquinazolin-4-yl)-1, 4-diazepane-1-carboxylate

To a stirred solution of 4-chloro-6, 7-dimethoxyquinazoline 1 (2 g,8.904 mmol) in acetonitrile (25 ml) were added potassium carbonate (2.4g, 17.809 mmol) and tert-butyl 1,4-diazepane-1-carboxylate 2 (1.96 g,9.795 mmol) then stirred at 80° C. for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction,reaction mixture completely distilled off under reduced pressure. Crudewas purified through combi-flash chromatography by eluting 5% methanolin dichloromethane to afford tert-butyl 4-(6,7-dimethoxyquinazolin-4-yl)-1, 4-diazepane-1-carboxylate 3 (2.7 g, 6.958mmol, 78% yield) as a pale yellow solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 7.14 (s, 1H),7.25 (s, 1H), 3.97-3.94 (t, 2H), 3.89-3.84 (m, 8H), 3.59 (d, 2H), 3.41(s, 2H), 1.98 (s, 2H), 1.15 (d, 9H).

Step-2: 4-(1, 4-diazepan-1-yl)-6, 7-dimethoxyquinazoline hydrochloride

To a stirred solution of tert-butyl4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylate 3 (200 mg,0.742 mmol) in dioxane (2 ml) was added 4M HCl in dioxane (8 mL) at 0°C. then stirred at room temperature for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, organicsolvents completely distilled off under reduced pressure. Crude waspurified by trituration with diethyl ether (20 mL) to afford 4-(1,4-diazepan-1-yl)-6, 7-dimethoxyquinazoline hydrochloride 4 (115 mg,0.355 mmol, 68% yield) as a yellow solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 9.33 (s, 2H), 8.79 (s, 1H),7.43 (s, 1H), 7.35 (s, 1H), 4.19 (s, 2H), 4.29 (s, 2H), 3.97-3.93 (m,6H), 3.17 (d, 2H), 2.77-2.31 (m, 2H).

Step-3: Tert-butyl ((4-(6, 7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl) sulfonyl) carbamate

To a stirred solution of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinazolinehydrochloride 4 (500 mg, 1.508 mmol) in dichloromethane (10 ml) wereadded diisopropylethylamine (0.5 mL, 2.262 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium5 (508 mg, 1.508 mmol) at 0° C. then stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After completionof the reaction, reaction mixture completely distilled off under reducedpressure to afford crude compound. Crude was purified through 100-200silica gel column chromatography by eluting 5% methanol indichloromethane to afford semi pure compound. This semi pure was againpurified by trituration with 50% ethyl acetate in pet ether to affordtert-butyl ((4-(6, 7-dimethoxyquinazolin-4-yl)-1, 4-diazepan-1-yl)sulfonyl) carbamate 6 (350 mg, 0.686 mmol, 44% yield) as an off whitesolid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 11.07 (brs, 1H), 8.18 (s, 1H),7.21 (s, 1H), 3.88-3.95 (m, 10H), 3.65-3.68 (t, 2H), 3.42-3.45 (t, 2H),2.06 (d, 2H), 1.33-1.36 (s, 9H). LCMS: (M+H+): m/Z: 468.15

Step-4: 4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamidehydrochloride salt (Compound 015-HCl)

To a stirred solution of tert-butyl((4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate6 (300 mg, 0.646 mmol) in dioxane (2 ml) was added 4M HCl in dioxane (8mL) at 0° C. then stirred at room temperature for 6 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction,organic solvents completely distilled off under reduced pressure. Crudewas purified by trituration with 5% methanol in dichloromethane (50 mL)to afford 4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamidehydrochloride salt (120 mg, 0.327 mmol, 51% yield) as an off whitesolid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.75 (s, 1H), 7.43 (s, 1H),7.34 (s, 1H), 6.84 (s, 1H), 4.18-4.22 (m, 4H), 3.94 (s, 3H), 3.96 (s,3H), 3.59 (m, 2H), 3.28-3.31 (t, 2H), 2.08 (brs, 2H).

LCMS: (M+H+): m/Z: 368.1

Synthetic Scheme of Compound 015-MES4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamidemethanesulfonate (015-MES)

To a stirred solution of4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamide (100 mg,0.272 mmol) (Compound 015 free base was prepared from the HCl salt bystirring with triethylamine for two hours) in acetonitrile (2 ml) andwater was added methane sulfonic acid (26 mg, 0.272 mmol) then reactionmixture kept under lyophilisation for 16 h to afford 4-(6,7-dimethoxyquinazolin-4-yl)-1, 4-diazepane-1-sulfonamide methanesulfonate (Compound 015-MES) (115 mg, 0.248 mmol, 91% yield) as an offwhite solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 14.150 (bs, 1H), 8.699 (s,1H), 7.401 (s, 1H), 7.183 (s, 1H), 6.819 (s, 1H), 4.141-4.166 (m, 4H),3.961 (s, 3H), 3.930 (s, 3H), 3.559-3.591 (m, 2H), 3.320 (m, 2H), 2.279(s, 3H), 2.061-2.103 (m, 2H).

LCMS: (M+H⁺): m/Z: 368.16.

Synthetic Scheme for Compound 016

Synthesis of Tert-butyl4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepane-1-carboxylate (3)

To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile1 (750 mg, 3.0 mmol) in acetonitrile (15 ml) was added potassiumcarbonate (834 mg, 6.0 mmol) and tert-butyl 1,4-diazepane-1-carboxylate2 (904 mg, 4.5 mmol) then stirred at 80° C. for 16 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction, tothe reaction mixture added water (100 mL) and extracted with ethylacetate (2×100 mL). Combined organic layers were washed with brinesolution (100 mL), dried over sodium sulfate and concentrated underreduced pressure. Crude compound was purified through combi flashchromatography to afford pure compound of tert-butyl4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepane-1-carboxylate (450mg, 1.09 mmol, 38% yield) as a light yellow solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 7.39 (s, 1H),7.31 (s, 1H), 3.94 (s, 6H), 3.59-3.62 (m, 6H), 3.46-3.3.53 (m, 2H), 2.05(s, 2H), 1.43 (s, 9H).

LCMS: (M+H)⁺: m/Z: 413.2

Synthesis of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrilehydrochloride (4)

To a stirred solution of tert-butyl4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepane-1-carboxylate 3(450 mg, 1.09 mmol) in dioxane (2 ml) was added 4M HCl in dioxane (3 mL)at 0° C. then stirred at room temperature for 4 h. The progress of thereaction was monitored by TLC. After completion of the reaction, organicsolvents completely distilled off under reduced pressure. To the cruderesidue was washed with ether to afford4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrilehydrochloride 4 (400 mg, 1.28 mmol, 92% yield) as a yellow solid.

LCMS: (M+H)⁺: m/Z: 313.31

Synthesis of Tert-butyl((4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate(6)

To a stirred solution of4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrilehydrochloride (4) (150 mg, 0.48 mmol) in dichloromethane (3 mL) wereadded diisopropylethylamine (0.25 mL, 1.44 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium5 (243 mg, 0.72 mmol) at RT, then stirred at room temperature for 16 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified combiflash column chromatography by eluting 60% ethyl acetate in pet-ether toafforded tert-butyl((4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate(6) (100 mg, 0.203 mmol, 42% yield) as a yellow solid.

Analytical Data: ¹HNMR (400 MHz, DMSO) δ 11.07 (s, 1H), 8.69 (S, 1H),7.39 (s, 1H), 7.34 (s, 1H), 3.92-3.94 (s, 6H), 3.58-3.68 (m, 8H), 2.08(m, 2H), 1.43 (s, 9H).

LCMS: (M+H)⁺: m/Z: 492.24

Preparation of Compound 016

To a stirred solution of tert-butyl((4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate(6) (100 mg, 0.203 mmol) in 1,4-dioxane (2.0 mL) was added 4M HCl indioxane (2.0 mL) at RT. Reaction mixture was stirred at RT for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified throughprep HPLC method to afford pure compound of Compound 016 (35 mg, 0.089mmol, 41% yield) as a pale yellow solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 7.37 (d, 2H),6.83 (s, 2H), 3.94 (s, 6H), 3.63-3.67 (m, 4H), 3.44-3.51 (m, 4H), 2.08(m, 2H).

LCMS: (M+H)⁺: m/Z: 392.2

Synthetic Scheme for Compound 017

Synthesis of Methyl 4-(4-(N-(tert-butoxycarbonyl) sulfamoyl)-1,4-diazepan-1-yl)-6-methoxyquinazoline-7-carboxylate (2)

To a stirred solution of 4-(4-(N-(tert-butoxycarbonyl) sulfamoyl)-1,4-diazepan-1-yl)-6-methoxyquinazolin-7-yl trifluoromethanesulfonate 1(200 mg, 0.342 mmol) in N, N′-dimethylformamide (2 mL) and methanol (10mL) were added triethylamine (103.6 mg, 1.026 mmol) was then degassedthe reaction mixture for 30 minutes. Then palladium (II) acetate (3.8mg, 0.017 mmol) and Xantphos (10 mg, 0.017 mmol) were added againdegassed for 5 minutes and stirred the reaction mixture under CO gasballoon pressure at 80° C. for 6 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, reaction mixturecompletely distilled off under reduced pressure, to the crude addedethyl acetate (50 mL) and filtered through celite. Washed the celite bedwith excess ethyl acetate (50 mL). Then added water (100 mL) andextracted. Organic layer washed with brine solution (100 mL), dried oversodium sulfate and concentrated under reduced pressure. Crude waspurified prep HPLC method to afford methyl 4-(4-(N-(tert-butoxycarbonyl)sulfamoyl)-1, 4-diazepan-1-yl)-6-methoxyquinazoline-7-carboxylate (2)(70 mg, 0.141 mmol, 41%) as a brown solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 8.493 (s, 1H), 7.952 (s, 1H),7.392 (s, 1H), 4.008-4.024 (m, 4H), 3.938 (s, 3H), 3.865 (s, 3H),3.691-3.718 (t, 2H), 3.446-3.476 (t, 2H), 2.099 (m, 2H), 1.363 (s, 9H).

Synthesis of Methyl6-methoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinazoline-7-carboxylatehydrochloride (Int-4)

A stirred solution of methyl 4-(4-(N-(tert-butoxycarbonyl) sulfamoyl)-1,4-diazepan-1-yl)-6-methoxyquinazoline-7-carboxylate 2 (70 mg, 0.545mmol) and 4M HCl in dioxane (4 mL) was stirred at room temperature for16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, organic solvents completely distilled offunder reduced pressure. Crude was purified by trituration with 5%methanol in dichloromethane (5 mL) to afford methyl6-methoxy-4-(4-sulfamoyl-1, 4-diazepan-1-yl) quinazoline-7-carboxylatehydrochloride Int-4 (55 mg, 0.127 mmol, 90% yield) as an off whitesolid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 8.486 (s, 1H), 7.948 (s, 1H),7.406 (s, 1H), 3.990-4.040 (m, 4H), 3.937 (s, 3H), 3.865 (s, 3H),3.523-3.548 (t, 2H), 3.274-3.293 (t, 2H), 2.103 (m, 2H).

LCMS: (M+H⁺): m/Z: 396.1

Synthesis of6-methoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinazoline-7-carboxylic Acid(Compound 017)

To a stirred solution of methyl6-methoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinazoline-7-carboxylatehydrochloride (Int-4) (55 mg, 0.139 mmol) in tetrahydrofuran (3 ml) andwater (1 mL) was added lithium hydroxide monohydrate (29 mg, 0.696 mmol)at 0° C. then stirred at room temperature for 16 h. After completion ofthe reaction organic solvents distilled off under reduced pressure. Tothe crude residue added water (20 mL) and acidified with 30% of citricacid solution (10 mL). Then extracted with 10% methanol indichloromethane (50 mL) and concentrated under reduced pressure toafford crude compound. Crude compound was purified through Prep HPLCmethod to afford pure compound6-methoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinazoline-7-carboxylic acidCompound 017 (10 mg, 0.03 mmol, 11% yield) as an off white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 13.237 (bs, 1H), 8.470 (s,1H), 7.848 (bs, 1H), 7.363 (s, 1H), 6.787 (s, 1H), 3.980-4.033 (m, 4H),3.923 (s, 3H), 3.522-3.547 (t, 2H), 3.280 (t, 2H), 2.072-2.102 (m, 2H).

LCMS: (M+H⁺): m/Z: 382

Synthetic Scheme for Compound 018

Synthesis of Tert-butyl4-(7-(benzyloxy)-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylate(3)

To a stirred solution of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline 1(250 mg, 0.831 mmol) in acetonitrile (5 ml) were added potassiumcarbonate (229 mg, 1.66 mmol) and tert-butyl 1,4-diazepane-1-carboxylate2 (249 mg, 1.24 mmol) then stirred at 80° C. for 16 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction, tothe reaction mixture added water and solid formed. Collect the solid byfiltration to afford pure compound of tert-butyl4-(7-(benzyloxy)-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylate(3) (380 mg, 0.818 mmol, 98%) as a white solid.

LCMS: (M+H)⁺: m/Z: 465.3

Tert-butyl4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylate (4)

To a stirred solution of tert-butyl4-(7-(benzyloxy)-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylate(3) (400 mg, 0.862 mmol) in Methanol (3 mL) and EtOAc (2 mL) were added10% Pd/C (40 mg) and stirred the reaction mixture under balloon hydrogenatmosphere at room temperature for 6 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, reaction mixturefiltered through celite and washed the celite bed with 5% methanol indichloromethane (50 mL). Filtrate was concentrated under reducedpressure to afforded tert-butyl4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylate (4)(300 mg, 0.802 mmol, 98% yield) as a light blue solid.

LCMS: (M+H⁺): m/Z: 375.2

Synthesis of Tert-butyl4-(7-(2-amino-2-oxoethoxy)-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylate(6)

To a stirred solution of tert-butyl4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylate 4(250 mg, 0.668 mmol) in acetonitrile (5 mL) were added potassiumcarbonate (276 mg, 2.0 mmol) and 2-bromoacetamide 5 (184 mg, 1.33 mmol)then stirred at 80° C. for 16 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, to the reactionmixture added water (100 mL) and extracted with ethyl acetate (2×100mL). Combined organic layers were washed with brine solution (100 mL),dried over sodium sulfate and concentrated under reduced pressure. Crudecompound was purified through combi flash chromatography to afford purecompound of tert-butyl4-(7-(2-amino-2-oxoethoxy)-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylate6 (200 mg, 0.462 mmol, 71% yield) as a light brown syrup.

LCMS: (M+H⁺): m/Z: 432.3

Synthesis of2-((4-(1,4-diazepan-1-yl)-6-methoxyquinazolin-7-yl)oxy)acetamidehydrochloride (7)

To a stirred solution of tert-butyl4-(7-(2-amino-2-oxoethoxy)-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylate6 (200 mg, 0.462 mmol) in dioxane (1 ml) was added 4M HCl in dioxane (2mL) at 0° C. then stirred at room temperature for 2 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction,organic solvents completely distilled off under reduced pressure. To thecrude residue was washed with ether to afford2-((4-(1,4-diazepan-1-yl)-6-methoxyquinazolin-7-yl)oxy)acetamidehydrochloride 7 (150 mg, 0.451 mmol, 88% yield) as a yellow solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 9.23 (br s, 1H), 8.77 (s, 1H),7.46-7.47 (m, 1H), 7.01-7.26 (m, 2H), 4.74 (s, 3H), 4.19-4.26 (m, 4H),3.94 (s, 3H), 3.71 (d, 2H), 3.45 (m, 2H), 3.18-3.3.19 (m, 2H), 2.24 (m,2H).

Synthesis of Tert-butyl((4-(7-(2-amino-2-oxoethoxy)-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate(8)

To a stirred solution of2-((4-(1,4-diazepan-1-yl)-6-methoxyquinazolin-7-yl)oxy)acetamidehydrochloride (7) (150 mg, 0.451 mmol) in dichloromethane (3 mL) wasadded diisopropylethylamine (0.24 mL, 1.36 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium5 (168 mg, 0.49 mmol) at RT, then stirred at room temperature for 16 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified combiflash column chromatography by eluting 60% ethyl acetate in pet-ether toafford tert-butyl((4-(7-(2-amino-2-oxoethoxy)-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate(9) (150 mg, 0.294 mmol, 65% yield) as a yellow solid.

LCMS: (M+H)⁺: m/Z: 511.2

Synthesis of Compound 018

To a stirred solution of tert-butyl((4-(7-(2-amino-2-oxoethoxy)-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate(9) (150 mg, 0.294 mmol) in 1,4-dioxane (1.0 mL) was added 4M HCl indioxane (2.0 mL) at RT. Reaction mixture was stirred at RT for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified throughprep HPLC method to afford pure compound of Compound 018 (15 mg, 0.036mmol, 12% yield) as an Off-white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 8.39 (s, 1H), 7.42-7.47 (dd,2H), 7.26 (s, 1H), 7.03 (s, 1H), 6.77 (s, 1H), 4.63 (s, 2H), 3.91-3.97(m, 7H), 3.48-3.51 (m, 2H), 3.24-3.27 (m, 3H), 2.05-2.08 (m, 2H).

LCMS: (M+H)⁺: m/Z: 411.1

Synthetic Scheme for Compounds 019, 020, 021, and 022

Synthesis of 7-(benzyloxy)-4-(1,4-diazepan-1-yl)-6-methoxyquinazolinehydrochloride (2)

A stirred solution of tert-butyl4-(7-(benzyloxy)-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-carboxylate 1(1 g, 2.155 mmol) and 4M HCl in dioxane (10 mL) was stirred at roomtemperature for 1 h. The progress of the reaction was monitored by TLC.After completion of the reaction, organic solvents completely distilledoff under reduced pressure. Crude was purified by trituration withpentane (50 mL) to afford7-(benzyloxy)-4-(1,4-diazepan-1-yl)-6-methoxyquinazoline hydrochloride 2(600 mg, 1.5 mmol, 70% yield) as an off white solid.

Analytical Data:

LCMS: (M+H⁺): m/Z: 365.2

Synthesis of Tert-butyl((4-(7-(benzyloxy)-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate(6)

To a stirred solution of7-(benzyloxy)-4-(1,4-diazepan-1-yl)-6-methoxyquinazoline hydrochloride 2(1 g, 2.497 mmol) in dichloromethane (20 mL) was addeddiisopropylethylamine (805 mg, 6.242 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium3 (841 mg, 2.497 mmol) at 0° C. then stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After completionof the reaction, reaction mixture completely distilled off under reducedpressure to afford crude compound. Crude was purified through 100-200silica gel column chromatography by eluting 5% methanol indichloromethane to afford semi pure compound. This semi pure was againpurified by trituration with 50% ethyl acetate in pet ether to affordtert-butyl((4-(7-(benzyloxy)-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate4 (1.2 g, 2.21 mmol, 89% yield) as an off white solid.

Analytical Data: LCMS: (M+H⁺): m/Z: 544.15

Synthesis of Tert-butyl((4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate(5)

To a stirred solution of tert-butyl((4-(7-(benzyloxy)-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate4 (1.2 g, 2.21 mmol) in ethanol (30 mL) was added 10% Pd/C (200 mg) andstirred the reaction mixture under balloon hydrogen atmosphere at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion, reaction mixture filtered through celite and washedthe celite bed with 5% methanol in dichloromethane (100 mL). Filtratewas concentrated under reduced pressure to afford semi pure compound oftert-butyl((4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate(5) (1.1 g, crude) as an off white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 10.341 (bs, 1H), 8.345 (s,1H), 7.205 (s, 1H), 7.027 (s, 1H), 4.330-4.356 (t, 2H), 3.890-3.924 (m,5H), 3.661 (t, 2H), 2.054-2.061 (m, 1H), 1.247-1.366 (m, 9H).

Synthesis of 4-(4-(N-(tert-butoxycarbonyl) sulfamoyl)-1,4-diazepan-1-yl)-6-methoxyquinazolin-7-yl trifluoromethanesulfonate (7)

To a stirred solution of tert-butyl((4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate5 (1.1 g, 2.428 mmol) in dichloromethane (15 mL) was added triethylamine(0.85 mL, 6.07 mmol) and1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide6 (1.3 g, 3.642 mmol) at 0° C. then stirred at room temperature 4 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, organic solvents completely distilled off under reducedpressure and water (200 mL) was added to the crude and partitioned withdichloromethane (2×200 mL). Combined organic layers were washed withbrine solution (200 mL), dried over sodium sulfate and concentratedunder reduced pressure. Crude was purified by combi-flash chromatographyby eluting 70% ethyl acetate in pet ether to afford4-(4-(N-(tert-butoxycarbonyl) sulfamoyl)-1,4-diazepan-1-yl)-6-methoxyquinazolin-7-yl trifluoromethanesulfonate 7(750 mg, 1.282 mmol, 58% yield over two steps) as an off white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 11.021 (s, 1H), 8.514 (s, 1H),7.847 (s, 1H), 7.566 (s, 1H), 3.990-4.031 (m, 8H), 3.707 (s, 2H), 3.443(s, 2H), 2.080 (bs, 2H), 1.342 (s, 9H).

Synthesis of4-(6-methoxy-7-(1H-pyrrol-3-yl)quinazolin-4-yl)-1,4-diazepane-1-sulfonamide(Compound 019)

In a sealed tube, to the stirred solution of4-(4-(N-(tert-butoxycarbonyl) sulfamoyl)-1,4-diazepan-1-yl)-6-methoxyquinazolin-7-yl trifluoromethanesulfonate 7(200 mg, 0.342 mmol) in dioxane (7 mL) and water (2 mL) were added(1-(triisopropylsilyl)-1H-pyrrol-3-yl)boronic acid (119 mg, 0.446 mmol)and cesium fluoride (104 mg, 0.684 mmol) was then degassed the reactionmixture for 30 minutes. Then tetrakis(triphenylphosphine)palladium(0)(20 mg, 0.0017 mmol) was added again degassed for 5 minutes and stirredthe reaction mixture at 65° C. for 3 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, reaction mixture waspoured into water (100 mL) and filtered through celite. Washed thecelite bed with 10% methanol in dichloromethane (100 mL) and separatedthe two layers. Organic layer washed with brine solution (200 mL), driedover sodium sulfate and concentrated under reduced pressure. Crude waspurified prep HPLC method to afford4-(6-methoxy-7-(1H-pyrrol-3-yl)quinazolin-4-yl)-1,4-diazepane-1-sulfonamide(Compound 019) (30 mg, 0.074 mmol, 22%) as a brown solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 10.984 (s, 1H), 8.332 (s, 1H),8.180 (s, 1H), 7.832 (s, 1H), 7.493 (s, 1H), 7.288 (s, 1H), 6.833 (s,1H), 6.650 (s, 1H), 3.838 (m, 8H), 3.499 (t, 2H), 3.251-3.277 (t, 2H),2.068 (m, 2H).

LCMS: (M+H⁺): m/Z: 403.1

Synthetic Scheme for Compounds 023, 024 and 025

Step-1: Synthesis of ethyl4-(4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxylate3

To a stirred solution of ethyl4-chloro-6,7-dimethoxyquinoline-3-carboxylate 1 (4.2 g, 4.2 mmol) in DMF(40 mL) was added tert-butyl 1,4-diazepane-1-carboxylate (4.2 ml, 4.2mmol) and K₂CO₃ (3.9 g, 28 mmol) then heated to 80° C. for refluxed for16 h. The progress of the reaction was monitored by TLC. Aftercompletion of reaction, reaction mixture was directly poured on to icecold water and stirred. Solid precipitated out was filtered and washedagain with water and dried without necessity of any further purificationto afford ethyl4-(4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxylate3 (5.5 g) as a light yellow solid.

Analytical Data: ¹H NMR (400 MHz, DMSO): 8.68 (s, 1H), 7.43 (s, 1H),7.37 (s, 1H), 4.34 (q, 2H), 3.93 (s, 6H), 3.59-3.54 (m, 4H), 3.26-3.19(m, 4H), 1.97-1.92 (m, 2H), 1.43-1.32 (m, 11H).

LCMS: (M+H)⁺: m/Z: 247.1

Step-2: Synthesis of ethyl4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxylate hydrochloride4

To a stirred solution of4-(4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxylate3 (5.5 g, 1.8 mmol) in 1,4 Dioxane (50 mL) was added 4.0M HCl in1,4-Dioxane (50 ml) slowly at 0° C. and slowly allowed to RT and stirredfor 2 h. After completion of reaction, volatile organics were removedunder reduced pressure, co-distilled thrice with DCM and triturated withether to give off-white solid ethyl4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxylate hydrochloride4 (4.2 g). The progress of the reaction was monitored by TLC.

Analytical Data: LCMS: (M+H)⁺: m/Z: 360

Step-3: ethyl4-(4-(N-(tert-butoxycarbonyl)sulfamoyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxylate6

To a stirred solution of4-((4-aminobutyl)thio)-6,7-dimethoxyquinoline-3-carbonitrile 4 (2 g,5.56 mmol) in DCM (30 mL) was addedN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminiumchloride 5 (2.06 g, 6.1 mmol) slowly and then added DIPEA (2.68 ml,0.375 mmol) at same temperature. Then stirred the reaction mixture atroom temperature for 16 h. The progress of the reaction was monitored byTLC. Reaction mixture was directly absorbed on to silica and convertedinto slurry. Crude was purified through combi-flash chromatography byeluting 90% EtOAc in Hexane to afford ethyl4-(4-(N-(tert-butoxycarbonyl)sulfamoyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxylate6 (1.1 g) as a white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO): 8.72 (s, 1H), 7.49 (s, 1H),7.37 (s, 1H), 4.36 (q, 2H), 3.93 (s, 6H), 3.59-3.52 (m, 4H), 3.22-3.09(m, 4H), 1.97-1.96 (m, 2H), 1.47 (s, 9H), 1.36 (t, 3H).

LCMS: (M+H)⁺: m/Z: 539.2

Step-4: Synthesis of ethyl6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxylate 7(compound 023)

To a stirred solution of ethyl4-(4-(N-(tert-butoxycarbonyl)sulfamoyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carboxylate7 (300 mg, 0.56 mmol) in dichloromethane (3 ml) was added TFA (3 mL) at0° C., then stirred at same temperature for 4 h. The progress of thereaction was monitored by TLC. After completion of reaction, TFA wasneutralized by using aq.NaHCO₃, and extracted with 10% MeOH/DCM anddried and concentrated. Obtained solid was triturated to give ethyl6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxylate 7Compound 023 (250 mg) as pale yellow solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ: 8.72 (s, 1H), 7.54 (s, 1H),7.37 (s, 1H), 6.79 (s, 2H), 4.36 (q, 2H), 3.93 (s, 6H), 3.44-3.43 (m,4H), 3.42-3.33 (m, 4H), 1.97-1.96 (m, 2H), 1.36 (t, 3H).

LCMS: (M+H)⁺: m/Z: 439.2

Step-5: Synthesis of6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxylicacid Compound 024

To a stirred solution of ethyl6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxylate 1(250 mg, 0.57 mmol) in THF:H₂O (3:1) was added LiOH (119 mg, 2.85 mmol)at RT. After addition, the reaction mixture was allowed to stir at RTfor 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of reaction, volatile organics were evaporated and trituratedwith ether to give 169 mg of6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxylicacid 7. 69 mg of 7 was submitted for prep-HPLC. After HPLC purification,6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxylicacid Compound 024 (26 mg) was obtained as a pale yellow solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ: 13.36 (brs, 1H), 8.74 (s,1H), 7.53 (s, 1H), 7.35 (s, 1H), 6.79 (s. 1H), 3.93 (s, 6H), 3.45-3.38(m, 8H), 1.95 (brs, 2H).

LCMS: (M+H)⁺: m/Z: 411.2

Step-6: Synthesis of6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxamideCompound 025

To a stirred solution of6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxylicacid 1 (100 mg, 0.24 mmol) in THF (3 ml) was added SOCl₂ (0.026 ml, 0.36mmol) at 0° C. After 1 h, the reaction mixture was purged with NH₃ (gas)at same temperature for 10 min and allowed to stir at RT for 16 h. Theprogress of the reaction was monitored by TLC. After completion ofreaction, Precipitate in the in the reaction mixture was washed with 10%MeOH/DCM and filtrate was dried and reduced to give crude about 85 mg.After HPLC purification,6,7-dimethoxy-4-(4-sulfamoyl-1,4-diazepan-1-yl)quinoline-3-carboxamideCompound 025 (9 mg) was obtained as a pale yellow solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) d: 8.50 (s, 1H), 7.99 (brs, 1H),7.57 (brs, 1H), 7.46 (s, 1H), 7.33 (s, 1H), 6.77 (s, 2H), 3.93-3.91 (m,6H), 3.45-3.42 (m, 4H), 3.37-3.35 (m, 4H), 1.95 (brs, 2H).

Synthesis of4-(6-methoxy-7-(1H-pyrazol-4-yl)quinazolin-4-yl)-1,4-diazepane-1-sulfonamide(Compound 020)

In a sealed tube, to the stirred solution of4-(4-(N-(tert-butoxycarbonyl) sulfamoyl)-1,4-diazepan-1-yl)-6-methoxyquinazolin-7-yl trifluoromethanesulfonate 7(100 mg, 0.171 mmol) in dioxane (5 mL) and water (1.5 mL) were addedtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate9 (65 mg, 0.222 mmol) and cesium fluoride (78 mg, 0.513 mmol) was thendegassed the reaction mixture for 30 minutes. Thentetrakis(triphenylphosphine)palladium(0) (20 mg, 0.0017 mmol) was addedagain degassed for 5 minutes and stirred the reaction mixture at 90° C.for 6 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, reaction mixture filtered through celite.Washed the celite bed with ethyl acetate (100 mL). Then added water (100mL) and extracted with excess ethyl acetate (100 mL). Organic layerwashed with brine solution (100 mL), dried over sodium sulfate andconcentrated under reduced pressure. Crude was purified prep HPLC methodto afford4-(6-methoxy-7-(1H-pyrazol-4-yl)quinazolin-4-yl)-1,4-diazepane-1-sulfonamide(Compound 020) (10 mg, 0.024 mmol, 15%) as a brown solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 13.134 (s, 1H), 8.457 (s, 1H),8.273 (s, 1H), 8.233 (s, 1H), 7.751 (bs, 1H), 7.405 (s, 1H), 6.916 (s,1H), 6.799 (s, 1H), 3.996-4.042 (m, 8H), 3.534-3.555 (t, 2H),2.097-2.141 (t, 2H), 2.068 (m, 2H).

LCMS: (M+H⁺): m/Z: 404.2.

Synthesis of4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamidehydrochloride (Compound 021)

A stirred solution of tert-butyl((4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate5 (100 mg, 0.221 mmol) and 4M HCl in dioxane (3 mL) was stirred at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, organic solvents completely distilledoff under reduced pressure. Crude was purified through prep HPLC methodto afford4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamidehydrochloride (Compound 021) (600 mg, 1.5 mmol, 70% yield) as an offwhite solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 14.348 (bs, 1H), 11.608 (s,1H), 8.693 (s, 1H), 7.415 (s, 1H), 7.245 (s, 1H), 6.842 (s, 2H),4.176-4.200 (m, 4H), 3.933 (s, 3H), 3.555-3.580 (m, 2H), 3.275-3.301 (t,2H), 2.078 (m, 2H).

LCMS: (M+H⁺): m/Z: 354.1.

Synthesis of 4-(6-methoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamide(Compound 022)

In a sealed tube, to the stirred solution of4-(4-(N-(tert-butoxycarbonyl) sulfamoyl)-1,4-diazepan-1-yl)-6-methoxyquinazolin-7-yl trifluoromethanesulfonate 7(100 mg, 0.171 mmol) in N, N′-dimethylformamide (2 mL) were added formicacid 9 (0.064 mL, 1.196 mmol), triethylamine (34 mg, 0.342 mmol) wasthen degassed the reaction mixture for 30 minutes. Then palladium (II)acetate (2 mg, 0.0085 mmol) and Xantphos (5 mg, 0.0085 mmol) were addedagain degassed for 5 minutes and stirred the reaction mixture at 100° C.for 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, reaction mixture filtered through celite.Washed the celite bed with ethyl acetate (100 mL). Then added water (100mL) and extracted with excess ethyl acetate (100 mL). Organic layerwashed with brine solution (100 mL), dried over sodium sulfate andconcentrated under reduced pressure. Crude was purified prep HPLC methodto afford 4-(6-methoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamide(Compound 022) (10 mg, 0.024 mmol, 15%) as a brown solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 8.444 (s, 1H), 7.704-7.727 (d,1H), 7.447-7.477 (dd, 1H), 7.310-7.316 (d, 1H), 6.789 (s, 2H),3.953-4.013 (m, 4H), 3.891 (s, 3H), 3.521-3.534 (t, 2H), 3.268-3.296 (t,2H), 2.088-2.096 (m, 2H).

LCMS: (M+H⁺): m/Z: 338

Synthetic Scheme of Compounds 026 and 027

Synthesis of4-(3,6-diazabicyclo[3.2.1]octan-3-yl)-6,7-dimethoxyquinazoline compoundwith 4-(3,6-diazabicyclo[3.2.1]octan-6-yl)-6,7-dimethoxyquinazoline (3 &3A)

To a stirred solution of 4-chloro-6, 7-dimethoxyquinazoline 1 (1 g,4.891 mmol) in t-BuOH (120 mL) were added cesium carbonate (5.6 g,17.119 mmol) and 3, 6-diazabicyclo [3.2.1]octane 2 (900 mg, 4.891 mmol)then stirred at room temperature for 16 h. The progress of the reactionwas monitored by TLC. After completion of the reaction, to the reactionmixture completely distilled off under reduced pressure. Crude waspurified by trituration with diethyl ether to afford4-(3,6-diazabicyclo[3.2.1]octan-3-yl)-6,7-dimethoxyquinazoline compoundwith 4-(3,6-diazabicyclo[3.2.1]octan-6-yl)-6,7-dimethoxyquinazoline (3 &3A) (1.1 g crude) as a white solid.

LCMS: (M+H⁺): m/Z: 301.2

Synthesis of Tert-butyl((3-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octan-6-yl)sulfonyl)carbamate(5) & Tert-butyl((6-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octan-3-yl)sulfonyl)carbamate(5A)

To a stirred solution of4-(3,6-diazabicyclo[3.2.1]octan-3-yl)-6,7-dimethoxyquinazoline compoundwith 4-(3,6-diazabicyclo[3.2.1]octan-6-yl)-6,7-dimethoxyquinazoline (3 &3A) (1.1 g, 3.666 mmol) in dichloromethane (20 mL) was addeddiisopropylethylamine (0.95 mL, 5.499 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium4 (1.23 g, 3.66 mmol) at 0° C. then stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After completionof the reaction, reaction mixture completely distilled off under reducedpressure to afford crude compound. Crude was purified through 100-200silica gel column chromatography by eluting 3% methanol indichloromethane to afford pure compounds of isomers tert-butyl((3-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octan-6-yl)sulfonyl)carbamate(5) (500 mg, 1.041 mmol, 28% yield) & tert-butyl((6-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octan-3-yl)sulfonyl)carbamate(5A) (150 mg, 0.312 mmol, 8% yield) as an off white solids.

Analytical Data

Cpd-5: ¹H NMR (400 MHz, DMSO) δ 8.324 (s, 1H), 8.144 (s, 1H),6.732-7.616 (m, 3H), 4.853-4.920 (dt, 1H), 4.287-4.351 (m, 1H),4.127-4.155 (d, 1H), 3.961-3.989 (d, 1H), 3.896 (s, 7H), 3.588-3.616 (d,1H), 3.413-3.439 (d, 1H), 3.174-3.199 (d, 1H), 2.886-3.012 (dd, 1H),2.713-2.771 (m, 2H), 2.004 (m, 2H), 1.650-1.785 (dd, 1H), 1.117-1.287(d, 8H).

LCMS: (M+H⁺): m/Z: 480.2

Cpd-5B: ¹H NMR (400 MHz, DMSO) δ 10.965-10.971 (brs, 1H), 8.700-8.718(d, 1H), 7.680-7.725 (d, 1H), 7.211 (s, 1H), 6.793 (s, 1H), 5.027-5.102(d, 1H), 4.515-4.526 (m, 1H), 4.026-4.120 (d, 1H), 3.944-3.959 (d, 6H),3.439-3.575 (d, 1H), 3.102-3.251 (m, 3H), 2.844-2.942 (m, 2H),2.045-2.072 (m, 1H), 1.757-1.912 (s, 1H), 1.232 (s, 5H).

LCMS: (M+H⁺): m/Z: 480.2

Synthesis of3-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octane-6-sulfonamidehydrochloride (Compound 026)

A stirred solution of tert-butyl((3-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octan-6-yl)sulfonyl)carbamate5 (100 mg, 0.208 mmol) and 4M HCl in dioxane (4 mL) was stirred at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, organic solvents completely distilledoff under reduced pressure. Crude was purified by trituration with 5%methanol in dichloromethane (50 mL) to afford3-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octane-6-sulfonamidehydrochloride Compound 026 (70 mg, 0.168 mmol, 81% yield) as an offwhite solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 14.287 (bs, 1H), 8.743 (s,1H), 7.740 (s, 1H), 7.26 (s, 1H), 6.812 (s, 2H), 5.118 (s, 1H),4.483-4.536 (bs, 1H), 4.148 (s, 1H), 3.966 (s, 3H), 3.971 (s, 3H),3.826-3.847 (d, 1H), 3.441-3.470 (d, 1H), 2.919-2.947 (d, 1H), 2.856(brs, 2H), 2.050-2.077 (m, 1H), 1.768-1.797 (d, 1H).

LCMS: (M+H⁺): m/Z: 380.2

Synthesis of6-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octane-3-sulfonamidehydrochloride (Compound 027)

A stirred solution of tert-butyl((6-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octan-3-yl)sulfonyl)carbamate5A (100 mg, 0.208 mmol) and 4M HCl in dioxane (4 mL) was stirred at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, organic solvents completely distilledoff under reduced pressure. Crude was purified by trituration with 5%methanol in dichloromethane (50 mL) to afford6-(6,7-dimethoxyquinazolin-4-yl)-3,6-diazabicyclo[3.2.1]octane-3-sulfonamidehydrochloride Compound 027 (70 mg, 0.168 mmol, 81% yield) as an offwhite solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 14.229 (bs, 1H), 8.724 (s,1H), 7.733 (s, 1H), 7.243 (s, 1H), 6.802 (s, 2H), 5.111 (s, 1H), 4.498(bs, 1H), 4.113-4.116 (d, 1H), 3.971 (s, 6H), 3.832-3.854 (d, 1H),3.444-3.469 (d, 1H), 2.919-2.946 (d, 1H), 2.825-2.853 (brs, 2H),2.046-2.074 (m, 1H), 1.764-1.793 (d, 1H).

LCMS: (M+H⁺): m/Z: 380.1

Synthetic Scheme for Compound 028 Synthesis of4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamide (Compound028)

To a stirred solution of tert-butyl((4-(7-hydroxy-6-methoxyquinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate1 (200 mg, 0.441 mmol) in N, N′-dimethylformamide (5 mL) and water (5mL) were added 2-chloro-2,2-difluoroacetic acid, sodium salt (335 mg,2.207 mmol) and cesium carbonate (719 mg, 2.205 mmol) then stirred thereaction mixture at 100° C. for 16 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, to the reactionmixture added water (100 mL), and extracted with ethyl acetate (2×50mL). Combined organic layers was washed with brine solution (100 mL),dried over sodium sulfate and concentrated under reduced pressure. Crudewas purified prep HPLC method to afford4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepane-1-sulfonamide (Compound028) (10 mg, 0.027 mmol, 5%) as an off white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 8.460 (s, 1H), 7.425-7.470 (m,3H), 6.796 (s, 2H), 3.979-4.001 (m, 4H), 3.959 (s, 3H), 3.509-3.535 (t,2H), 3.261-3.289 (t, 2H), 2.084 (m, 2H).

LCMS: (M+H⁺): m/Z: 404.1

Synthetic Scheme of Compound 029

Synthesis of 4-(6,6-difluoro-1,4-diazepan-1-yl)-6,7-dimethoxyquinazoline(3)

To a stirred solution of 4-chloro-6, 7-dimethoxyquinazoline 1 (160 mg,0.695 mmol) in t-butanol (25 mL) were added potassium carbonate (288 mg,2.085 mmol) and 6,6-difluoro-1,4-diazepane 2 (218 mg, 1.043 mmol) thenstirred at room temperature for 16 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturecompletely distilled off under reduced pressure. To the crude added 10%methanol in dichloromethane and filtered. Filtrate was concentratedunder reduced pressure to afford4-(6,6-difluoro-1,4-diazepan-1-yl)-6,7-dimethoxyquinazoline (3) (180 mg,crude) as an off white solid.

LCMS: (M+H⁺): m/Z: 325.2

Synthesis of tert-butyl((4-(6,7-dimethoxyquinazolin-4-yl)-6,6-difluoro-1,4-diazepan-1-yl)sulfonyl)carbamate(5)

To a stirred solution of4-(6,6-difluoro-1,4-diazepan-1-yl)-6,7-dimethoxyquinazoline (3) (150 mg,0.463 mmol) in dichloromethane (5 ml) were added diisopropylethylamine(90 mg, 0.694 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium4 (171 mg, 0.509 mmol) at 0° C. then stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After completionof the reaction, reaction mixture completely distilled off under reducedpressure to afford crude compound. Crude was purified through 100-200combi-flash chromatography by eluting 3% methanol in dichloromethane toafford tert-butyl((4-(6,7-dimethoxyquinazolin-4-yl)-6,6-difluoro-1,4-diazepan-1-yl)sulfonyl)carbamate(5) (200 mg, 0.397 mmol, 86% yield) as an off white solid.

LCMS: (M+H⁺): m/Z: 504.2

Synthesis of4-(6,7-dimethoxyquinazolin-4-yl)-6,6-difluoro-1,4-diazepane-1-sulfonamidehydrochloride (Compound 029)

A stirred solution of tert-butyl((4-(6,7-dimethoxyquinazolin-4-yl)-6,6-difluoro-1,4-diazepan-1-yl)sulfonyl)carbamate5 (170 mg, 0.338 mmol) and 4M HCl in dioxane (10 mL) was stirred at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, organic solvents completely distilledoff under reduced pressure. Crude was purified by trituration with 5%methanol in dichloromethane (5 mL) to afford4-(6,7-dimethoxyquinazolin-4-yl)-6,6-difluoro-1,4-diazepane-1-sulfonamidehydrochloride Compound 029 (20 mg, 0.045 mmol, 13% yield) as an offwhite solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 8.558 (s, 1H), 7.251 (s, 1H),7.181 (s, 1H), 7.098 (s, 2H), 4.388-4.456 (t, 2H), 3.935 (s, 6H),3.878-3.903 (t, 3H), 3.789-3.822 (d, 2H), 3.720-3.755 (m, 2H).

LCMS: (M+H⁺): m/Z: 404.22

Synthetic Scheme for Compound 030

Synthesis of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline (3)

To a stirred solution of 4-chloro-6,7-dimethoxyquinoline 1 (2 g, 8.9686mmol) in ethanol (20 ml) were added potassium carbonate (2.4 g, 17.9372mmol) and 1,4-diazepane 2 (2.7 g, 26.9058 mmol) then stirred at 90° C.temperature for 4 days. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture completelydistilled off under reduced pressure. To the crude added 10% methanol indichloromethane and filtered. Filtrate was concentrated under reducedpressure to afford 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline (3) (1g) as an off white solid.

Analytical Data:

LCMS: (M+H⁺): m/Z: 288.2.

Synthesis of Tert-butyl((4-(6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate(5)

To a stirred solution of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline(3) (150 mg, 0.0522 mmol) in dichloromethane (5 mL) were addeddiisopropylethylamine (0.13 mL, 0.7839 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium4 (176 mg, 0.0522 mmol) at 0° C. then stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After completionof the reaction, reaction mixture completely distilled off under reducedpressure to afford crude compound. Crude was purified through 100-200combi-flash chromatography by eluting 3% methanol in dichloromethane toafford Tert-butyl((4-(6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate(5) (100 mg, 41% yield) as an off white solid.

Analytical Data:

LCMS: (M+H⁺): m/Z: 466.13

Synthesis of 4-(6,7-dimethoxyquinolin-4-yl)-1,4-diazepane-1-sulfonamide(Compound 030)

A stirred solution of Tert-butyl((4-(6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate 5(90 mg, 0.1931 mmol) and 4M HCl in dioxane (5 mL) was stirred at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, organic solvents completely distilledoff under reduced pressure. Crude was purified by trituration with 5%methanol in dichloromethane (5 mL) to afford4-(6,7-dimethoxyquinolin-4-yl)-1,4-diazepane-1-sulfonamide Compound 030(40 mg, 57% yield) as an off white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 8.42 (d, 1H), 7.40 (s, 1H),7.35 (s, 1H), 6.98 (d, 1H), 6.86 (s, 2H), 3.94-3.99 (m, 10H), 3.56 (t,2H), 2.13 (s, 2H).

LCMS: (M+H⁺): m/Z: 367.28

Synthetic Scheme of Compound 031

Synthesis of4-(1,4-diazepan-1-yl)-6,7-dimethoxy-2-(trifluoromethyl)quinazoline (3)

To a stirred solution of4-chloro-6,7-dimethoxy-2-(trifluoromethyl)quinazoline 1 (150 mg, 0.512mmol) in t-butanol (10 ml) were added potassium carbonate (71 mg, 0.512mmol) and 1,4-diazepane 2 (102 mg, 1.025 mmol) then stirred at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture completelydistilled off under reduced pressure. To the crude added 10% methanol indichloromethane and filtered. Filtrate was concentrated under reducedpressure to afford4-(1,4-diazepan-1-yl)-6,7-dimethoxy-2-(trifluoromethyl)quinazoline (3)(170 mg, crude) as an off white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 7.380 (s, 1H), 7.312 (s, 1H),3.903-3.969 (m, 10H), 3.044-3.069 (t, 2H), 2.793-2.820 (t, 2H), 1.947(bs, 2H).

Synthesis of Tert-butyl((4-(6,7-dimethoxy-2-(trifluoromethyl)quinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate(5)

To a stirred solution of4-(1,4-diazepan-1-yl)-6,7-dimethoxy-2-(trifluoromethyl)quinazoline (3)(150 mg, 0.421 mmol) in dichloromethane (5 ml) were addeddiisopropylethylamine (81 mg, 0.632 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium4 (142 mg, 0.421 mmol) at 0° C. then stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After completionof the reaction, reaction mixture completely distilled off under reducedpressure to afford crude compound. Crude was purified through 100-200combi-flash chromatography by eluting 3% methanol in dichloromethane toafford tert-butyl ((4-(6, 7-dimethoxy-2-(trifluoro methyl)quinazolin-4-yl)-1, 4-diazepan-1-yl) sulfonyl) carbamate (5) (190 mg,0.355 mmol, 84% yield) as an off white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 11.094 (bs, 1H), 7.330 (d,2H), 4.009-4.019 (m, 4H), 3.940 (s, 3H), 3.924 (s, 3H), 3.699-3.712 (t,3H), 3.435 (t, 2H), 2.072 (bs, 2H), 1.343 (s, 9H).

Synthesis of4-(6,7-dimethoxy-2-(trifluoromethyl)quinazolin-4-yl)-1,4-diazepane-1-sulfonamidehydrochloride (Compound 031)

A stirred solution of tert-butyl((4-(6,7-dimethoxy-2-(trifluoromethyl)quinazolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate5 (160 mg, 0.299 mmol) and 4M HCl in dioxane (10 mL) was stirred at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, organic solvents completely distilledoff under reduced pressure. Crude was purified by trituration with 5%methanol in dichloromethane (5 mL) to afford4-(6,7-dimethoxy-2-(trifluoromethyl)quinazolin-4-yl)-1,4-diazepane-1-sulfonamidehydrochloride Compound 031 (100 mg, 0.212 mmol, 71% yield) as an offwhite solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 7.340 (s, 1H), 6.802 (bs, 2H),3.992-4.040 (m, 4H), 3.939 (s, 3H), 3.924 (s, 3H), 3.516-3.556 (t, 2H),3.261-3.289 (t, 2H), 2.063-2.090 (m, 2H).

LCMS: (M+H⁺): m/Z: 436.33

General Scheme 6:

Example 6: (N-(2-(4-(6, 7-dimethoxyquinazolin-4-yl)-1, 4-diazepan-1-yl)ethyl) sulfamide hydrochloride Step-IA: 2-(4-(6,7-dimethoxyquinazolin-4-yl)-1, 4-diazepan-1-yl) acetonitrile

To a stirred solution of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinazoline1 (1 g, 3.472 mmol) in N,N′-dimethylformamide (10 ml) were addedpotassium carbonate (1.4 g, 10.416 mmol) and 2-bromoacetonitrile (0.83g, 6.944 mmol) then stirred at 90° C. for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction,reaction mixture completely distilled off under reduced pressure. Crudewas purified through combi-flash chromatography by eluting 80% ethylacetate in pet ether to afford 2-(4-(6, 7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl) acetonitrile 2 (0.93 g, 2.844 mmol, 68% yield) as apale brown solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 7.27 (s, 1H),7.14 (s, 1H), 3.87 (s, 3H), 3.90 (s, 3H), 3.94-3.92 (m, 4H), 3.79 (s,2H), 2.93 (t, 2H), 2.69-2.66 (m, 2H), 2.05-2.04 (m, 2H). LCMS: (M+H+):m/Z: 328.2

Step-1B: 3-(4-(6, 7-dimethoxyquinazolin-4-yl)-1, 4-diazepan-1-yl)propanenitrile

To a stirred solution of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinazoline1 (1 g, 3.472 mmol) in ethanol (15 ml) was added acrylonitrile (0.68 mL,10.416 mmol) then stirred at 45° C. for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction,reaction mixture completely distilled off under reduced pressure. Crudewas purified through combi-flash chromatography by eluting 5% methanolin dichloromethane to afford 3-(4-(6, 7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl) propanenitrile 3 (1 g, 2.932 mmol, 85% yield) as areddish colored gummy liquid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 7.26 (s, 1H),7.13 (t, 2H), 3.89-3.85 (m, 10H), 2.96-2.94 (m, 2H), 2.74-2.69 (m, 4H),2.65-2.62 (m, 2H), 2.00 (m, 2H).

LCMS: (M+H)+: m/Z: 342.2

Step-2: 2-(4-(6, 7-dimethoxyquinazolin-4-yl)-1, 4-diazepan-1-yl)ethan-1-amine

To a stirred solution of2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)acetonitrile 2(900 mg, 2.752 mmol) in 1,4-dioxane (18 mL) and water (10 ml) were addedlithium hydroxide monohydrate (231 mg, 5.504 mmol), Raney Ni (936 mg)and 10% Pd/C (295 mg) and stirred the reaction mixture under balloonhydrogen atmosphere at room temperature for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction,reaction mixture filtered through celite and washed the celite bed with10% methanol in dichloromethane (100 mL). Filtrate was concentratedunder reduced pressure to afford crude compound. Crude was purifiedthrough Grace reverse phase column chromatography by eluting 20%acetonitrile in 0.1% formic acid in water to afford 2-(4-(6,7-dimethoxyquinazolin-4-yl)-1, 4-diazepan-1-yl) ethan-1-amine 3 (100 mg,0.302, 11%) as a reddish brown gummy liquid.

Analytical Data: LCMS: (M+H+): m/Z: 332.24

The following compound was synthesized by the above general procedure:

Structure 1HNMR

1H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 8.23 (brs, 2H), 7.26 (s, 1H),7.13 (s, 1H), 3.89- 3.87 (m, 10H), 2.87 (m, 2H), 2.82-2.78 (t, 2H),2.66-2.61 (m, 2H), 2.00 (m, 2H), 1.68-1.65 (m, 2H). MS 346.2

Step-3: Tert-butyl (N-(2-(4-(6, 7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl) ethyl) sulfamoyl) carbamate

To a stirred solution of2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)ethan-1-amine 3(100 mg, 0.302 mmol) in dichloromethane (5 ml) were addeddiisopropylethylamine (60 mg, 0.453 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminiumchloride 4 (102 mg, 0.302 mmol) at 0° C. then stirred at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, reaction mixture completely distilledoff under reduced pressure to afford crude compound. Crude was purifiedthrough combi-flash column chromatography by eluting 5% methanol indichloromethane to afford tert-butyl (N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1, 4-diazepan-1-yl) ethyl) sulfamoyl)carbamate 5 (90 mg, 0.176 mmol, 58% yield) as a brown solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 7.26 (s, 1H),7.18 (m, 1H), 7.14 (s, 1H), 3.89-3.87 (d, 10H), 3.00-2.97 (m, 4H),2.75-2.68 (m, 2H), 2.66-2.62 (m, 2H), 2.04-2.01 (m, 2H), 1.39 (s, 9H).LCMS: (M+H+): m/Z: 511.21

The following compound was synthesized by the above general procedure

Structure 1HNMR

1HNMR (400 MHz, DMSO) δ 8.37 (s, 1H), 7.60 (brs, 1H), 7.26 (s, 1H), 7.13(s, 1H), 3.89-3.87 (m, 10H), 2.90-2.89 (m, 4H), 2.66 (m, 2H), 2.01 (m,2H), 1.63-1.60 (t, 2H), 1.39 (s, 9H). MS 525.3

Step-4: (N-(2-(4-(6, 7-dimethoxyquinazolin-4-yl)-1, 4-diazepan-1-yl)ethyl) sulfamide hydrochloride (Compound 063)

To a stirred solution of tert-butyl(N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)ethyl)sulfamoyl)carbamate5 (90 mg, 0.176 mmol) in dioxane (2 ml) was added 4M HCl in dioxane (8mL) at 0° C. then stirred at room temperature for 6 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction,organic solvents completely distilled off under reduced pressure. Crudewas purified through prep HPLC method to afford (N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1, 4-diazepan-1-yl) ethyl) sulfamidehydrochloride (15 mg, 0.036 mmol, 72% yield) as an off white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 7.26 (s, 1H),7.14 (s, 1H), 6.56 (brs, 2H), 6.26-6.27 (brs, 1H), 3.90-3.87 (m, 10H),2.99-96 (m, 4H), 2.03 (m, 2H). LCMS: (M+H+): m/Z: 411.2

Compound Number Structure 1HNMR 063

1H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 7.26 (s, 1H), 7.13 (s, 1H), 6.44(m, 3H), 3.89-3.87 (m, 10H), 2.89-2.87 (m, 4H), 2.62-2.60 (m, 2H), 1.99(m, 2H), 1.62-1.58 (t,2H). MS 425.2

Compound 062 was also prepared based on the general procedure describedabove:

1H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 7.26 (s, 1H), 7.14 (s, 1H), 6.56(brs, 2H), 6.26-6.27 (brs, 1H), 3.90-3.87 (m, 10H), 2.99-96 (m, 4H),2.03 (m, 2H). LCMS 411.2. MW 446.95.

Synthetic Scheme of Compound 032

Synthesis of4-(4-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile(3)

To a stirred solution of4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrilehydrochloride 1 (500 mg, 1.6 mmol) in DMF (5 ml) was added potassiumcarbonate (662 mg, 4.8 mmol) and 2-(2-bromoethyl)isoindoline-1,3-dione 2(610 mg, 1.76 mmol) then stirred at 90° C. for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction,reaction mixture was poured on water and extracted with ethyl acetate.Organic layer was separated and washed with water, then organic layerwas concentrated under reduced pressure to obtained crude. Crude residuewas purified by combi-flash chromatography to afforded pure compound of4-(4-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile(3) (300 mg, 0.618 mmol, 38% yield) as a brown syrup.

LCMS: (M+H)⁺: m/Z: 486.2

Synthesis of4-(4-(2-aminoethyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile(4)

To a stirred solution of4-(4-(2-aminoethyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile3 (300 mg, 0.61 mmol) in EtOH (6 mL) was added 90% of hydrazine hydrate(0.06 mL, 1.23 mmol) at RT, then reaction mixture was stirred at refluxfor 2 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, reaction mixture was poured on water andextracted with ethyl acetate. Organic layer was separated and washedwith water, Organic layer was concentrated under reduced pressure toobtain crude. Crude compound was purified by combi-flash chromatographyto afford pure compound of4-(4-(2-aminoethyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile(4) (100 mg, 0.281 mmol, 45% yield) as a brown syrup.

LCMS: (M+H)⁺: m/Z: 356.3

Synthesis of Tert-butyl(N-(2-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-l)ethyl)sulfamoyl)carbamate(6)

To a stirred solution of4-(4-(2-aminoethyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile(4) (100 mg, 0.28 mmol) in dichloromethane (2 mL) were addeddiisopropylethylamine (0.146 mL, 0.84 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium5 (95 mg, 0.28 mmol) at RT, then stirred at room temperature for 16 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified combiflash column chromatography by eluting 5% MeOH in DCM to affordtert-butyl(N-(2-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)ethyl)sulfamoyl)carbamate(6) (80 mg, 0.225 mmol, 53% yield) as a brown thick syrup.

LCMS: (M+H)⁺: m/Z: 535.19

Synthesis of Compound 032

To a stirred solution of tert-butyl(N-(2-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)ethyl)sulfamoyl)carbamate(6) (80 mg, 0.182 mmol) in 1,4-dioxane (1.0 mL) was added 4M HCl indioxane (2 mL) at RT. Reaction mixture was stirred at RT for 6 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified throughprep HPLC method to afford pure compound of Compound 032 (15 mg, 0.034mmol, 23% yield) as an off white solid Analytical Data: ¹H NMR (400 MHz,DMSO) δ 8.62 (s, 1H), 8.17 (s, 1H), 7.37 (s, 2H), 6.57 (brs, 2H), 6.30(t, 1H), 3.94 (d, 6H), 3.71-3.7 (m, 4H), 3.0-3.05 (m, 2H), 2.84-2.89 (m,4H), 2.67-2.71 (m, 2H), 1.98-2.01 (m, 2H).

LCMS: (M+H)⁺: m/Z: 435.2

Synthetic Scheme for Compound 033

Synthesis of4-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile(3)

To a stirred solution of4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrilehydrochloride 1 (500 mg, 1.6 mmol) in DMF (5 mL) were added potassiumcarbonate (662 mg, 4.8 mmol) and 2-(3-bromopropyl)isoindoline-1,3-dione2 (515 mg, 1.9 mmol) then stirred at 90° C. for 16 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction,reaction mixture was poured on water and extracted with ethyl acetate.Organic layer was separated and washed with water, then organic layerwas concentrated under reduced pressure to obtained crude. Crude residuewas purified by combi-flash chromatography to afforded pure compound of4-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile3 (150 mg, 0.30 mmol, 19% yield) as a brown syrup.

LCMS: (M+H)⁺: m/Z: 500.34

Synthesis of4-(4-(3-aminopropyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile(4)

To a stirred solution of4-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile3 (150 mg, 0.3 mmol) in EtOH (3 mL) were added 90% of hydrazine hydrate(0.03 mL, 0.6 mmol) at RT, then reaction mixture was stirred at refluxfor 4 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, reaction mixture was poured on water andextracted with ethyl acetate. Organic layer was separated and washedwith water, Organic layer was concentrated under reduced pressure toobtain crude. Crude compound was purified by combi-flash chromatographyto afford pure compound of4-(4-(3-aminopropyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile(4) (100 mg, 0.271 mmol, 90% yield) as a brown syrup.

LCMS: (M+H)⁺: m/Z: 370.2

Synthesis of Tert-butyl(N-(3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)propyl)sulfamoyl)carbamate(6)

To a stirred solution of4-(4-(3-aminopropyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrile(4) (100 mg, 0.27 mmol) in dichloromethane (2 ml) were addeddiisopropylethylamine (0.14 mL, 0.81 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium5 (91 mg, 0.27 mmol) at RT, then stirred at room temperature for 16 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified combiflash column chromatography by eluting 5% MeOH in DCM to affordtert-butyl(N-(3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)propyl)sulfamoyl)carbamate(6) (100 mg, 0.182 mmol, 67% yield) as a brown solid.

LCMS: (M+H)⁺: m/Z: 549.31

Synthesis of Compound 033

To a stirred solution of afford tert-butyl(N-(3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)propyl)sulfamoyl)carbamate(6) (100 mg, 0.182 mmol) in 1,4-dioxane (2.0 ml) was added 4M HCl indioxane (2 mL) at RT. Reaction mixture was stirred at RT for 6 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified throughprep HPLC method to afford pure compound of Compound 033 (10 mg, 0.022mmol, 12% yield) as an off white solid. Analytical Data: ¹H NMR (400MHz, DMSO) δ 8.60 (s, 1H), 7.30 (s, 1H), 7.36 (s, 2H), 6.47-6.53 (m,3H), 3.90 (d, 6H), 3.70-3.72 (m, 4H), 2.90-2.95 (m, 2H), 2.78-2.81 (m,4H), 2.54-2.57 (m, 2H), 1.98 (m, 2H), 1.61-1.68 (m, 2H).

LCMS: (M+H)⁺: m/Z: 449.2

Example 7: (N-(2-(4-(6, 7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl) sulfamide hydrochloride Step 1: Synthesisof tert-butyl(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)carbamate

To a stirred solution of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinazoline(400 mg, 1.38 mmol) in DMF (5 ml) was added DIPEA (0.85 mL, 4.83 mmol),TBTU (531 mg, 1.65 mmol) and (tert-butoxy carbonyl)glycine (267 mg, 1.52mmol) at room temperature. Reaction mixture was stirred at for 16 h.After completion of the reaction, reaction mixture was poured on waterand extracted with ethyl acetate. Organic layer was separated and washedwith water, Then organic layer was concentrated under reduced pressureto afford pure compound of tert-butyl(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)carbamate20 (410 mg, 0.921 mmol, 66% yield) as a brown solid. 1H NMR (400 MHz,DMSO) δ 8.41 (d, 1H), 7.21 (d, 1H), 7.16 (d, 1H), 6.72-6.69 (m, 1H),3.96-3.87 (m, 10H), 3.80-3.76 (m, 4H), 3.56-3.55 (m, 2H), 2.05-1.93 (m,2H), 1.36-1.33 (m, 9H). LCMS: (M+H)+: m/Z: 446.26

The following compound was synthesized by the above general procedure:

Structure 1HNMR

(400 MHz, DMSO) δ 8.40 (d, 1H), 7.22-7.21 (m, 1H), 7.16-7.15 (m, 1H),6.63-6.64 (m, 1H), 3.95-3.84 (m, 10H), 3.77-3.75 (m, 2H), 3.56-3.53 (m,2H), 3.08-3.06 (m, 2H), 2.45-2.43 (m, 2H), 2.02-1.92 (m, 2H), 1.33 (s,9H). MS 460.26

Step-2: 2-amino-1-(4-(6, 7-dimethoxyquinazolin-4-yl)-1, 4-diazepan-1-yl)ethan-1-one hydrochloride

To a stirred solution of tert-butyl(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)carbamate(3) (300 mg, 0.674 mmol) in dioxane (1 ml) was added 4M HCl in dioxane(3 mL) at RT, then stirred at room temperature for 16 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction,organic solvents completely distilled off under reduced pressure toafford 2-amino-1-(4-(6, 7-dimethoxyquinazolin-4-yl)-1, 4-diazepan-1-yl)ethan-1-one hydrochloride (4) (250 mg, 0.656 mmol, 91% yield) as a brownsolid.

Analytical data: 1H NMR (400 MHz, DMSO) δ 15.07 (brs, 1H), 8.77-8.78 (d,1H), 8.10 (brs, 3H), 7.47-7.41 (m, 2H), 4.28-4.19 (m, 4H), 4.00-3.84 (m,13H), 3.66-3.64 (m, 1H), 2.00-2.10 (m, 2H).

Structure 1HNMR

1H NMR (400 MHz, DMSO) δ 8.79-8.76 (d, 1H), 7.94-7.89 (m, 4H), 7.43-7.41(m, 2H), 4.27-4.20 (m, 4H), 3.96 (s, 6H), 3.88 (bs, 4H), 3.56-3.63 (m,2H), 2.93-2.87 (m, 1H), 2.67-2.65 (m, 1H), 2.08-2.00 (m, 2H). MS 360.2

Step-3: Tert-butyl (N-(2-(4-(6, 7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl) sulfamoyl) carbamate

To a stirred solution of2-amino-1-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)ethan-1-onehydrochloride (4) (250 mg, 0.724 mmol) in dichloromethane (20 ml) wereadded diisopropylethylamine (0.631 mL, 3.62 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminiumchloride 4 (293 mg, 0.869 mmol) at RT, then stirred at room temperaturefor 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, organic solvents completely distilled offunder reduced pressure to afford crude compound. Crude compound waspurified combi flash column chromatography by eluting 5% methanol in DCMto afford tert-butyl (N-(2-(4-(6, 7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl) sulfamoyl) carbamate 6 (200 mg, 0.381 mmol,52% yield) as a brown solid. LCMS: (M+H)+: m/Z: 525.2

Structure 1HNMR

1H NMR (400 MHz, DMSO) δ 10.79 (bs, 1H), 8.46-8.39 (m, 2H), 7.26-7.25(m, 1H), 7.21 (d, 1H), 7.16 (d, 1H), 6.96 (d, 1H), 3.90-3.88 (m, 10H),3.77-3.74 (m, 2H), 3.54 (t, 2H), 3.06-3.03 (m, 2H), 2.58-2.54 (m, 2H),2.09-1.90 (m, 2H), 1.39 (s, 9H). MS 539.3

Step-4: (N-(2-(4-(6, 7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl) sulfamide hydrochloride (Compound 064)

To a stirred solution of tert-butyl(N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)sulfamoyl)carbamate6 (200 mg, 0.381 mmol) in 1,4-dioxane (1.0 ml) was added 4M HCl indioxane (3 mL) at RT. Reaction mixture was stirred at RT for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified throughprep HPLC method to afford pure compound of (N-(2-(4-(6,7-dimethoxyquinazolin-4-yl)-1, 4-diazepan-1-yl)-2-oxoethyl) sulfamidehydrochloride (50 mg, 0.117 mmol, 31% yield) as an off white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.42 (d, 1H), 7.22-7.21 (d,1H), 7.16 (d, 1H), 6.59-6.55 (m, 2H), 6.15-6.14 (m, 1H), 3.98-3.97 (m,1H), 3.90-3.88 (m, 10H), 3.82-3.78 (m, 3H), 3.76-3.75 (m, 1H), 3.57-3.56(m, 2H), 2.10-1.95 (m, 2H). LCMS: (M+H)+: m/Z: 425.2

Compound Number Structure 1HNMR 064

1H NMR (400 MHz, DMSO) δ 8.41 (d, 1H), 7.21 (d, 1H), 7.16 (d, 1H), 6.53(s, 2H), 6.32-6.31 (m, 1H), 3.97-3.94 (m, 1H), 3.90-3.88 (m, 9H),3.78-3.74 (m, 2H), 3.06-3.03 (m, 2H), 2.59-2.52 (m, 2H), 2.04-1.94 (m,2H). MS 439.2

Compound 065 was also prepared based on the general synthesis above:

1H NMR (400 MHz, DMSO) δ 15.07 (brs, 1H), 8.77-8.78 (d, 1H), 8.10 (brs,3H), 7.47-7.41 (m, 2H), 4.28-4.19 (m, 4H), 4.00-3.84 (m, 13H), 3.66-3.64(m, 1H), 2.00-2.10 (m, 2H). LCMS 425.2. MW. 460.93

Synthetic Scheme for Compound 034

Synthesis of Tert-butyl(2-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)carbamate(3)

To a stirred solution of4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrilehydrochloride 1 (200 mg, 0.641 mmol) in DMF (4 mL) was added DIPEA(0.335 mL, 1.923 mmol), TBTU (247 mg, 0.769 mmol) and(tert-butoxycarbonyl)glycine (123 mg, 0.705 mmol) at room temperature.Reaction mixture was stirred at for 16 h. After completion of thereaction, reaction mixture was poured on water and extracted with ethylacetate. Organic layer was separated and washed with water, then organiclayer was concentrated under reduced pressure to obtain crude. Crudecompound was purified by combi-flash chromatography to afford tert-butyl(2-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)carbamate(3) (200 mg, 0.426 mmol, 66% yield) as a yellow solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 7.94 (s, 1H),7.4 (d, 1H), 7.26 (s, 1H), 6.73-6.77 (m, 1H), 4.02-4.00 (m, 8H),3.80-3.81 (m, 2H), 3.71 (m, 2H), 3.57 (m, 2H), 3.47-3.48 (m, 1H), 2.8(s, 2H), 2.1 (m, 2H), 1.38 (s, 9H).

Synthesis of4-(4-glycyl-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrilehydrochloride (4)

To a stirred solution of tert-butyl(2-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)carbamate3 (300 mg, 0.639 mmol) in dioxane (2 ml) was added 4M HCl in dioxane (3mL) at 0° C. then stirred at room temperature for 6 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction,organic solvents completely distilled off under reduced pressure. To thecrude residue was washed with ether to afford4-(4-glycyl-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrilehydrochloride 4 (250 mg, 0.677 mmol, 96% yield) as a yellow solid.

LCMS: (M+H)⁺: m/Z: 370.2

Synthesis of Tert-butyl(N-(2-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)sulfamoyl)carbamate(6)

To a stirred solution of4-(4-glycyl-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrilehydrochloride (4) (250 mg, 0.677 mmol) in dichloromethane (20 voL) wasadded diisopropylethylamine (0.354 mL, 2.03 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium5 (251 mg, 0.745 mmol) at RT, then stirred at room temperature for 16 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified combiflash column chromatography by eluting 60% ethyl acetate in pet-ether toafford tert-butyl(N-(2-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-2-oxoethyl)sulfamoyl)carbamate(6) (200 mg, 0.364 mmol, 54% yield) as a pale yellow solid.

LCMS: (M+H)⁺: m/Z: 549.34

Preparation of Compound 034

To a stirred solution of tert-butyl((4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)sulfonyl)carbamate(6) (100 mg, 0.203 mmol) in 1,4-dioxane (2.0 mL) was added 4M HCl indioxane (2.0 mL) at RT. Reaction mixture was stirred at RT for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified throughprep HPLC method to afford pure compound 034 (35 mg, 0.089 mmol, 41%yield) as a pale yellow solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.67-8.7 (d, 1H), 7.39-7.40(d, 1H), 7.26 (s, 1H), 6.62 (d, 2H), 6.14-6.15 (m, 1H), 3.92-3.94 (s,6H), 3.83 (m, 2H), 3.67-3.77 (m, 3H), 3.50-3.59 (m, 3H), 2.06-2.08 (m,2H).

LCMS: (M+H)⁺: m/Z: 449.2

Synthetic Scheme for Compound 035

Synthesis of Tert-butyl4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepane-1-carboxylate (3)

To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile1 (1.3 g, 5.22 mmol) in DMF (26 mL) were added potassium carbonate (1.45g, 10.44 mmol) and tert-butyl 1,4-diazepane-1-carboxylate 2 (1.57 g,7.84 mmol) then stirred at 80° C. for 16 h. The progress of the reactionwas monitored by TLC. After completion of the reaction, to the reactionmixture added water (100 mL) and extracted with ethyl acetate (2×100mL). Combined organic layers were washed with brine solution (100 mL),dried over sodium sulfate and concentrated under reduced pressure toafford pure compound of tert-butyl4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepane-1-carboxylate (1.5g, 3.64 mmol, 69% yield) as a white solid.

LCMS: (M+H)+: m/Z: 413.2

Synthesis of 4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrilehydrochloride (4)

To a stirred solution of tert-butyl4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepane-1-carboxylate 3(450 mg, 1.09 mmol) in dioxane (2 mL) was added 4M HCl in dioxane (3 mL)at 0° C. then stirred at room temperature for 4 h. The progress of thereaction was monitored by TLC. After completion of the reaction, organicsolvents completely distilled off under reduced pressure. To the cruderesidue was washed with ether to afford4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrilehydrochloride 4 (400 mg, 1.28 mmol, 92% yield) as a yellow solid.

LCMS: (M+H)⁺: m/Z: 313.31

Synthesis of Tert-butyl(3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-3-oxopropyl)carbamate(6)

To a stirred solution of4-(1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrilehydrochloride 4 (100 mg, 0.32 mmol) in DMF (2 ml) was added DIPEA (0.16mL, 0.96 mmol), TBTU (124 mg, 0.38 mmol) and3-((tert-butoxycarbonyl)amino)propanoic acid (66 mg, 0.35 mmol) at roomtemperature. Reaction mixture was stirred at for 16 h. After completionof the reaction, reaction mixture was poured on water and extracted withethyl acetate. Organic layer was separated and washed with water, thenorganic layer was concentrated under reduced pressure to obtain crude.Crude compound was purified by combi-flash chromatography to affordtert-butyl(3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-3-oxopropyl)carbamate(6) (100 mg, 0.154 mmol, 66% yield) as a light brown solid.

LCMS: (M+H)⁺: m/Z: 484.3

Synthesis of4-(4-(3-aminopropanoyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrilehydrochloride (7)

To a stirred solution of tert-butyl(3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-3-oxopropyl)carbamate7 (200 mg, 0.308 mmol) in dioxane (1 mL) was added 4M HCl in dioxane (2mL) at 0° C. then stirred at room temperature for 4 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction,organic solvents completely distilled off under reduced pressure. To thecrude residue was washed with ether to afford4-(4-(3-aminopropanoyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrilehydrochloride 7 (150 mg, 0.391 mmol, 91% yield) as a brown solid.

LCMS: (M+H)⁺: m/Z: 384.2

Synthesis of Tert-butyl(N-(3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-3-oxopropyl)sulfamoyl)carbamate(8)

To a stirred solution of4-(4-(3-aminopropanoyl)-1,4-diazepan-1-yl)-6,7-dimethoxyquinoline-3-carbonitrilehydrochloride (7) (150 mg, 0.39 mmol) in dichloromethane (3 mL) wereadded diisopropylethylamine (0.2 mL, 1.17 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium(145 mg, 0.43 mmol) at RT, then stirred at room temperature for 16 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified combiflash column chromatography by eluting 5% methanol in DCM to affordedtert-butyl(N-(3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-3-oxopropyl)sulfamoyl)carbamate(8) (150 mg, 0.266 mmol, 68% yield) as a brown solid.

LCMS: (M+H)⁺: m/Z: 563.3

Synthesis of Compound 035

To a stirred solution of tert-butyl(N-(3-(4-(3-cyano-6,7-dimethoxyquinolin-4-yl)-1,4-diazepan-1-yl)-3-oxopropyl)sulfamoyl)carbamate(8) (150 mg, 0.266 mmol) in 1,4-dioxane (1.0 mL) was added 4M HCl indioxane (2.0 mL) at RT. Reaction mixture was stirred at RT for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified throughprep HPLC method to afford pure compound of Compound 035 (30 mg, 0.064mmol, 24% yield) as a Off-white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.71 (d, 1H), 7.41 (d, 2H),7.27 (s, 1H), 6.56 (d, 2H), 6.34-6.40 (m, 1H), 3.92-3.94 (m, 6H),3.78-3.81 (m, 1H), 3.67-3.70 (m, 4H), 3.50-3.59 (m, 4H), 3.10-3.17 (m,2H), 2.65-2.70 (m, 2H), 2.06-2.07 (m, 2H). LCMS: (M+H)+: m/Z: 463.2

Example 8:N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)azepan-4-yl)ethyl)sulfamideStep-IA: tert-butyl 4-(cyanomethylene) azepane-1-carboxylate

To a stirred solution of tert-butyl 4-oxoazepane-1-carboxylate (500 mg,2.347 mmol) in tetrahydrofuran (10 mL) and triethylamine (475 mg, 4.694mmol) were added diethyl (cyanomethyl)phosphonate (436 mg, 2.464 mmol)and lithium bromide (245 mg, 2.816 mmol) at 0° C. Then stirred thereaction mixture at room temperature for 16 h. The progress of thereaction was monitored by TLC. After completion, reaction mixture waspoured into ice cold water (100 mL) and extracted with ethyl acetate(2×100 mL). Combined organic layers were washed with brine solution (100mL), dried over sodium sulfate and concentrated under reduced pressure.Crude was purified through 100-200 silica gel column chromatography byeluting 15% ethyl acetate in pet ether to afford tert-butyl4-(cyanomethylene)azepane-1-carboxylate (510 mg, 2.161 mmol, 92% yield)as a colorless oily liquid. 1HNMR (400 MHz, DMSO) δ 5.57-5.42 (m, 1H),3.43 (m, 2H), 3.32 (m, 1H), 3.29 (m, 1H), 2.72 (m, 1H), 2.59-2.50 (m,2H), 2.40 (d, 1H), 1.61 (m, 2H), 1.38 (s, 9H).

Step-1B: Tert-butyl 4-cyanoazepane-1-carboxylate

To a stirred solution of tert-butyl 4-oxoazepane-1-carboxylate 1 (250 g,1.173 mmol) in N, N′-dimethylformamide (1 ml) was added1-((isocyanomethyl) sulfonyl)-4-methylbenzene 2 (286 mg, 1.467 mmol) at0° C. To the reaction mixture was added the solution of potassiumtert-butoxide (262 mg, 2.346 mmol) in t-butanol (1 mL) and 1,2-dimethoxy ethane (1 mL) at 0° C. and stirred the reaction mixture atroom temperature for 3 h. The progress of the reaction was monitored byTLC. After completion, reaction mixture was poured into ice cold water(50 mL) and extracted with ethyl acetate (2×30 mL). Combined organiclayers were washed with brine solution (50 mL), dried over sodiumsulfate and concentrated under reduced pressure. Crude was purifiedthrough 100-200 silica gel column chromatography by eluting 15% ethylacetate in pet ether to afford tert-butyl 4-cyanoazepane-1-carboxylate 3(150 mg, 0.669 mmol, 57% yield) as a pale blue gummy liquid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 3.43-3.37 (m, 2H), 3.27-3.16(m, 2H), 3.07 (brs, 1H), 1.88-1.85 (m, 2H), 1.73 (brs, 4H), 1.38 (s,9H).

Step-2: Tert-butyl 4-(2-aminoethyl) azepane-1-carboxylate

To a stirred solution of tert-butyl4-(cyanomethylene)azepane-1-carboxylate 3 (510 mg, 2.161 mmol) in1,4-dioxane (15 mL) and water (5 ml) were added lithium hydroxidemonohydrate (200 mg, 4.754 mmol), Raney Ni (500 mg) and 10% Pd/C (150mg) and stirred the reaction mixture under balloon hydrogen atmosphereat room temperature for 16 h. The progress of the reaction was monitoredby TLC. After completion, reaction mixture filtered through celite andwashed the celite bed with 5% methanol in dichloromethane (100 mL).Filtrate was concentrated under reduced pressure to afford semi purecompound of tert-butyl 4-(2-aminoethyl) azepane-1-carboxylate 4 (500 mg,crude) as a colorless gummy liquid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 3.46-3.07 (m, 8H), 2.55-2.50(m, 2H), 1.76-1.66 (m, 3H), 1.60 (m, 1H), 1.43 (m, 3H), 1.27-1.14 (m,4H), 1.30-1.01 (m, 1H).

Structure 1HNMR

1H NMR (400 MHz, DMSO) δ 3.42-3.33 (m, 4H), 3.21-3.10 (m, 3H), 2.37-2.31(m, 2H), 1.81-1.73 (m, 4H), 1.42-1.37 (m, 12H), 1.22-1.15 (m, 1H),1.01-0.96 (m, 1H).

Step-3: Tert-butyl 4-(2-((N-(tert-butoxycarbonyl) sulfamoyl) amino)ethyl) azepane-1-carboxylate

To a stirred solution of tert-butyl4-(2-aminoethyl)azepane-1-carboxylate 4 (500 mg, 2.066 mmol) indichloromethane (10 ml) were added diisopropylethylamine (400 mg, 3.099mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium5 (696 mg, 2.066 mmol) at 0° C. then stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After completion,to the reaction mixture added water (100 mL) and extracted withdichloromethane (2×100 mL). Combined organic layers were washed withbrine solution (100 mL), dried over sodium sulfate and concentratedunder reduced pressure to afford crude compound. Crude was purifiedthrough 100-200 silica gel column chromatography by eluting 2% methanolin dichloromethane to afford semi pure compound. This semi pure waswashed with 50% ethyl acetate in pet ether to afford tert-butyl4-(2-((N-(tert-butoxycarbonyl) sulfamoyl) amino) ethyl)azepane-1-carboxylate 6 (600 mg, 1.425 mmol, 69% yield) as a colorlessgummy liquid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 10.76 (s, 1H), 7.50-7.45 (m,1H), 3.41 (m, 1H), 3.24-3.19 (m, 2H), 3.12-3.03 (m, 1H), 2.87 (d, 2H),1.70 (m, 2H), 1.57 (m, 1H), 1.39 (m, 25H).

Structure 1HNMR

1H NMR (400 MHz, DMSO) δ 10.79 (s, 1H), 7.64 (bs, 1H), 3.41-3.36 (m,2H), 3.09-3.20 (m, 2H), 2.66-2.72 (m, 2H), 1.71-1.74 (m, 3H), 1.52 (m,1H), 1.38 (s, 9H), 1.41 (s, 9H), 1.14 (t, 2H), 0.98 (d, 1H).

Step-4: (N-(2-(azepan-4-yl)ethyl)sulfamide

To a stirred solution of tert-butyl4-(2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)ethyl)azepane-1-carboxylate6 (600 mg, 1.425 mmol) in dioxane (5 ml) was added 4M HCl in dioxane (15mL) at 0° C. then stirred at room temperature for 3 h. The progress ofthe reaction was monitored by TLC. After completion, organic solventscompletely distilled off under reduced pressure to afford crude(N-(2-(azepan-4-yl)ethyl)sulfamide (420 mg, crude) as a pale brown gummysolid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.94 (d, 2H), 6.34 (broad s,2H), 3.07 (m, 2H), 2.96 (m, 2H), 2.86 (t, 2H), 1.76 (m, 3H), 1.64 (m,2H), 1.52-1.44 (m, 1H), 1.41-1.32 (m, 2H), 1.22 (m, 1H).

Structure 1HNMR

1H NMR (400 MHz, DMSO) δ 8.94 (s, 2H), 6.48 (bs, 1H), 6.61 (bs, 1H),3.17-3.15 (m, 1H), 3.06 (m, 1H), 2.96-2.94 (m, 2H), 2.76-2.65 (m, 2H),1.93-1.58 (m, 5H), 1.50-1.42(m, 1H), 1.20-1.17 (m, 1H).

Step-5:N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)azepan-4-yl)ethyl)sulfamide(Compound 060)

To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline 8 (285 mg,1.273 mmol) in acetonitrile (15 ml) were added potassium carbonate (263mg, 1.909 mmol) and compound-7 (360 mg, 1.4 mmol) then stirred at 90° C.for 16 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, added water (100 mL) and extracted withethyl acetate (2×100 mL). Combined organic layers were washed with brinesolution (100 mL), dried over sodium sulfate and concentrated underreduced pressure. Crude was purified through preparative HPLC method toafford N-(2-(1-(6,7-dimethoxyquinazolin-4-yl)azepan-4-yl)ethyl)sulfamide(52 mg, 0.127 mmol, 10% yield) as a pale orange solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 7.29 (s, 1H),7.12 (s, 1H), 6.43 (m, 3H), 3.97 (d, 2H), 3.88 (m, 6H), 3.68 (m, 2H),2.89 (m, 2H), 1.98 (m, 2H), 1.87 (m, 1H), 1.74 (m, 1H), 1.63 (m, 2H),1.44 (m, 2H), 1.22 (m, 1H).

Compound Number Structure 1HNMR 060

1HNMR (400 MHz, DMSO) δ: 8.36 (s, 1H), 7.29 (s, 1H), 7.12 (s, 1H), 6.56(t, 1H), 6.45 (s, 2H), 4.00-3.98 (m, 2H), 3.87 (s, 3H), 3.89 (s, 3H),3.68-3.64 (m, 2H), 2.74 (t, 2H), 2.03 (t, 2H), 1.83-1.82 (m, 2H),1.69-1.59 (m, 2H), 1.22-1.17 (m, 1H). MS 396.2

Compound 049 was prepared based on the general procedure describedabove:

M.W. 409.51

1H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 7.29 (s, 1H), 7.12 (s, 1H), 6.43(m, 3H), 3.97 (d, 2H), 3.88 (m, 6H), 3.68 (m, 2H), 2.89 (m, 2H), 1.98(m, 2H), 1.87 (m, 1H), 1.74 (m, 1H), 1.63 (m, 2H), 1.44 (m, 2H), 1.22(m, 1H). LCMS 409.9

Synthetic Scheme of Compound 036

Step-1: Synthesis of4-((2-(2-aminoethoxy)ethyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile3

To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile1 (150 mg, 0.68 mmol) in THF (15 mL) was added2,2′-oxybis(ethan-1-amine) 2 (314 mg, 3.4 mmol) then stirred thereaction mixture at 50° C. for 20 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, reaction mixturecompletely distilled off and absorbed onto celite and reverse phasegrace performed using AC N/Water system to afford4-((2-(2-aminoethoxy)ethyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile(170 mg) as a white solid.

Analytical Data: 1H NMR (400 MHz, DMSO): δ 8.36-8.33 (m, 3H), 8.09 (brs,1H), 7.75 (s, 1H), 7.21 (s, 1H), 3.95-3.94 (m, 2H), 3.90 (s, 6H), 3.75(t, 2H), 3.60 (t, 2H), 2.89 (t, 2H).

LCMS: (M+H)+: m/Z: 317.2

Step-2: Synthesis of tert-butyl(N-(2-(2-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)ethoxy)ethyl)sulfamoyl)carbamate 5

To a stirred solution of4-((2-(2-aminoethoxy)ethyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile3 (170 mg, 0.54 mmol) in DCM (10 mL) was addedN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminiumchloride 4 (163 mg, 0.48 mmol) slowly and then added DIPEA (0.3 ml, 1.6mmol) at same temperature. Then stirred the reaction mixture at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.Reaction mixture was directly absorbed on to silica and converted intoslurry. Crude was purified through combi-flash chromatography by eluting2-3% MeOH in DCM to afford tert-butyl(N-(2-(2-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)ethoxy)ethyl)sulfamoyl)carbamate5 (90 mg) as a white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ:10.84 (s, 1H), 8.34 (s, 1H),7.81 (brs, 1H), 7.64 (s, 1H), 7.51 (t, 1H), 7.21 (s, 1H), 3.93-3.89 (m,8H), 3.72 (t, 2H), 3.51 (t, 2H), 3.06-3.01 (m, 2H), 1.35 (s, 9H).

LCMS: (M+H)+: m/Z: 396

Step-3: Synthesis of Compound 036

To a stirred solution of tert-butyl(N-(2-(2-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)ethoxy)ethyl)sulfamoyl)carbamate5 (90 mg, 0.18 mmol) in dioxane (3 ml) was added 4M HCl in dioxane (1mL) at 0° C. then stirred at room temperature for 16 h. The progress ofthe reaction was monitored by TLC. After completion of reaction, organicsolvents completely distilled off under reduced pressure. Crude compoundwas purified by prep-HPLC to give Compound 036 (10 mg) as white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ: 8.34 (s, 1H), 7.84 (t, 1H),7.64 (s, 1H), 7.22 (s, 1H), 6.52 (brs, 2H), 6.45 (t, 1H) 3.94-3.89 (m,8H), 3.72 (t, 2H), 3.54 (t, 2H), 3.06 (q, 2H).

LCMS: (M+H)+: m/Z: 396.25.

Synthetic Scheme for Compound 037

Synthesis of4-((4-((N-(tert-butoxycarbonyl)sulfamoyl)amino)butyl)amino)-6-methoxyquinazolin-7-yltrifluoromethanesulfonate (Int-5)

To a stirred solution of Int-6 (500 mg, 1.13 mmol) in dichloromethane(20 ml) were added triethylamine (0.475 mL, 3.39 mmol) and1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide2 (445 mg, 1.24 mmol) at 0° C. then stirred at room temperature 4 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, organic solvents completely distilled off under reducedpressure and water (200 mL) was added to the crude and partitioned withdichloromethane (2×200 mL). Combined organic layers were washed withbrine solution (200 mL), dried over sodium sulfate and concentratedunder reduced pressure. Crude was purified by combi-flash chromatographyby eluting 70% ethyl acetate in pet ether to afford4-((4-((N-(tert-butoxycarbonyl)sulfamoyl)amino)butyl)amino)-6-methoxyquinazolin-7-yltrifluoromethanesulfonate Int-5 (450 mg, 0.785 mmol, 69% yield over twosteps) as a pale yellow solid.

LCMS: (M+H⁺): m/Z: 574.

Preparation of Compound 037

In a sealed tube, to the stirred solution of4-((4-((N-(tert-butoxycarbonyl)sulfamoyl)amino)butyl)amino)-6-methoxyquinazolin-7-yltrifluoromethanesulfonate Int-5 (200 mg, 0.349 mmol) in dioxane (8 mL)and water (2 mL) were added3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-pyrrole(121 mg, 0.453 mmol) and cesium fluoride (159 mg, 1.047 mmol) was thendegassed the reaction mixture for 30 minutes. Thentetrakis(triphenylphosphine)palladium(0) (40 mg, 0.034 mmol) was addedagain degassed for 5 minutes and stirred the reaction mixture at 100° C.for 5 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, reaction mixture was poured into water (100mL) and filtered through celite. Washed the celite bed with 10% methanolin dichloromethane (100 mL) and separated the two layers. Organic layerwashed with brine solution (200 mL), dried over sodium sulfate andconcentrated under reduced pressure. Crude was purified prep HPLC methodto afford (Compound 037) (30 mg, 0.052 mmol, 23%) as a pale yellowsolid.

Analytical Data: 1HNMR (400 MHz, DMSO) δ 11.13 (s, 1H), 8.625 (brs, 1h), 8.49 (s, 1H), 7.8 (s, 1H), 7.7 (s, 1H), 7.51 (s, 1H), 6.86-6.87 (m,1H), 6.62-63 (m, 1H), 6.46-6.52 (m, 3H), 4.0 (s, 3H), 3.59-3.61 (q, 2H),2.92-2.95 (q, 2H), 1.55-1.72 (m, 4H).

LCMS: (M+H⁺): m/Z: 391.1

Synthetic Scheme for Compound 038

To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile1 (100 mg, 0.403 mmol) in N,N′-dimethylformamide (5 ml) was addedpotassium carbonate (83 mg, 0.443 mmol) and compound-2 (114 mg, 0.443mmol) then stirred at 90° C. for 3 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, added water (100 mL)and extracted with ethyl acetate (2×100 mL). Combined organic layerswere washed with brine solution (100 mL), dried over sodium sulfate andconcentrated under reduced pressure. Crude was purified throughpreparative HPLC method to afford Compound 038 (29 mg, 0.067 mmol, 16%yield) as an off white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.618 (s, 1H), 7.365 (s, 1H),7.330 (s, 1H), 6.450-6.467 (d, 3H), 3.94 (s, 3H), 3.931 (s, 3H),3.671-3.689 (m, 2H), 3.554-3.587 (m, 2H), 2.903-2.953 (m, 2H),1.820-1.926 (m, 5H), 1.437-1.582 (m, 4H).

LCMS: (M+H+): m/Z: 434.2

Compound 038 was submitted for SFC and separated into two enantiomers toafford 038-Ent-1 (17 mg, 0.039 mmol) & 038-Ent-2 (17 mg, 0.039 mmol).

Analytical Data of 038-Ent-1: 1H NMR (400 MHz, DMSO) δ 8.628 (s, 1H),7.376 (s, 1H), 7.343 (s, 1H), 6.456 (bs, 3H), 3.951 (s, 3H), 3.942 (s,3H), 3.679-3.722 (t, 2H), 3.580-3.624 (m, 2H), 2.925-2.958 (t, 2H),1.835-1.935 (m, 5H), 1.423-1.591 (m, 4H).

LCMS: (M+H+): m/Z: 434.2

Analytical Data of 038-Ent-2: 1H NMR (400 MHz, DMSO) δ 8.627 (s, 1H),7.376 (s, 1H), 7.342 (s, 1H), 6.462 (bs, 3H), 3.950 (s, 3H), 3.941 (s,3H), 3.665-3.678 (m, 2H), 3.596-3.615 (m, 2H), 2.940-2.957 (t, 2H),1.836-2.060 (m, 5H), 1.507-1.523 (m, 4H).

LCMS: (M+H+): m/Z: 434.2

Synthetic Scheme for Compound 039

Synthesis of Preparation of Compound 039

To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile8 (150 mg, 0.605 mmol) in N,N′-dimethylformamide (3 ml) was addedpotassium carbonate (250 mg, 1.814 mmol) and compound-7 (220 mg, 0.907mmol) then stirred at 90° C. for 6 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, added water (100 mL)and extracted with ethyl acetate (2×100 mL). Combined organic layerswere washed with brine solution (100 mL), dried over sodium sulfate andconcentrated under reduced pressure. Crude was purified throughpreparative HPLC method to afford Compound 039 (170 mg, 0.405 mmol, 67%yield) as an off white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.625 (s, 1H), 7.368 (s, 1H),7.331 (s, 1H), 6.613-6.644 (t, 1H), 6.483 (s, 2H), 3.94 (s, 3H), 3.931(s, 3H), 3.544-3.3.688 (m, 4H), 2.788-2.848 (m, 2H), 1.937-2.045 (m,4H), 1.740-1.793 (m, 1H), 1.511-1.589 (m, 1H), 1.368-1.424 (m, 1H).

LCMS: (M+H+): m/Z: 420.2

Compound 039 was submitted for SFC and separated into two enantiomers toafford 039-Ent-1 (25 mg, 0.059 mmol) & 039-Ent-2 (17 mg, 0.04 mmol).

Analytical Data of 039-Ent-1: 1H NMR (400 MHz, DMSO) δ 8.635 (s, 1H),7.379 (s, 1H), 7.343 (s, 1H), 6.618-6.644 (t, 1H), 6.487 (s, 2H), 3.941(s, 3H), 3.951 (s, 3H), 3.645-3.672 (m, 4H), 2.801-2.843 (m, 2H),1.952-2.053 (m, 4H), 1.785-1.825 (m, 1H), 1.551-1.593 (m, 1H),1.390-1.456 (m, 1H).

LCMS: (M+H+): m/Z: 420.2

Analytical Data of 039-Ent-2: 1H NMR (400 MHz, DMSO) δ 8.636 (s, 1H),7.379 (s, 1H), 7.343 (s, 1H), 6.634 (bs, 1H), 6.488 (t, 1H), 6.487 (s,2H), 3.941 (s, 3H), 3.951 (s, 3H), 3.645-3.672 (m, 4H), 2.801-2.843 (m,2H), 1.952-2.055 (m, 4H), 1.765-1.825 (m, 1H), 1.553-1.573 (m, 1H),1.386-1.456 (m, 1H).

LCMS: (M+H⁺): m/Z: 420

Synthetic Scheme of Compound 040-Ent-1

Synthesis of 1-(6,7-dimethoxyquinazolin-4-yl)azepane-4-sulfonamide(Compound 040-Ent-1)

To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline 1 (120 mg,0.5357 mmol) in ACN (2 mL) and K2CO3 (222 mg, 1.6071 mmol), then stirredat 90° C. for 16 h. After completion of the reaction the crude residueadded water (10 mL). Then extracted with 10% methanol in dichloromethane(30 mL) and concentrated under reduced pressure to afford crudecompound. Crude compound was purified through Prep HPLC method to affordpure compound 1-(6,7-dimethoxyquinazolin-4-yl)azepane-4-sulfonamide(T-116-Ent-1) (10 mg, 5% yield) as an off white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 7.26 (s, 1H),7.15 (s, 1H), 6.74 (s, 2H), 4.09 (m, 2H), 3.90 (s, 3H), 3.88 (s, 3H),3.69-3.80 (m, 2H), 3.69 (m, 1H), 3.01 (p, 2H), 2.30 (m, 1H), 2.08 (p,2H), 1.91 (m, 1H), 1.60 (m, 1H).

LCMS: (M+H⁺): m/Z: 367.1

Synthetic Scheme for Compound 040-Ent-2

Synthesis of 1-(6,7-dimethoxyquinazolin-4-yl)azepane-4-sulfonamide(Compound 040-Ent-2)

To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline 1 (120 mg,0.5357 mmol) in ACN (2 mL) and K2CO3 (222 mg, 1.6071 mmol), then stirredat 90° C. for 16 h. After completion of the reaction the crude residueadded water (10 mL). Then extracted with 10% methanol in dichloromethane(30 mL) and concentrated under reduced pressure to afford crudecompound. Crude compound was purified through Prep HPLC method to affordpure compound 1-(6,7-dimethoxyquinazolin-4-yl)azepane-4-sulfonamide(T-116-Ent-2) (10 mg, 5% yield) as an off white solid.

Analytical Data: Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.50 (s, 1H),7.34 (s, 1H), 7.18 (s, 1H), 6.78 (s, 2H), 4.18 (m, 2H), 3.93 (s, 3H),3.91 (s, 3H), 3.76-3.84 (m, 2H), 3.04 (m, 1H), 3.01 (p, 2H), 2.92 (m,1H), 2.13 (m, 1H), 1.98 (m, 1H), 1.60 (m, 1H). LCMS: (M+H+): m/Z: 367.1

Synthetic Scheme for Compound 041

Synthesis of tert-butyl 4-methyleneazepane-1-carboxylate (2)

To a stirred solution of methyltriphenylphosphoniumbrimide 2 (227 mg,0.563 mmol) in diethyl ether (5 mL) was added 1M of potassiumtert-butoxide in t-butanol (63 mg, 0.563 mmol), reaction turns toyellow. Then added tert-butyl 4-oxoazepane-1-carboxylate 1 (100 mg,0.469 mmol) and stirred at 50° C. for 3 h. The progress of the reactionwas monitored by TLC. After completion of the reaction, to the reactionmixture added water (30 mL) and extracted with ethyl acetate (2×20 mL).Combined organic layers were washed with brine solution (40 mL), driedover sodium sulfate and concentrated under reduced pressure. Crudecompound was purified through 100-200 silica gel column chromatographyby eluting 5% ethyl acetate in pet ether to afford tert-butyl4-methyleneazepane-1-carboxylate 2 (60 mg, 0.284 mmol) as a colorlessoily liquid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 4.732-4.786 (m, 4H),2.404-2.433 (m, 2H), 2.209-2.239 (t, 2H), 1.655-1.706 (m, 2H), 1.448 (s,9H).

Synthesis of tert-butyl 4-(bromomethyl)-4-fluoroazepane-1-carboxylate(3)

To a stirred solution of tert-butyl 4-methyleneazepane-1-carboxylate 2(1.9 g, 9.005 mmol) in dichloromethane (50 mL) were added triethylaminetrihydrofluoride (3.6 g, 22.52 mmol) and N-bromo succinimide (2.4 g,13.507 mmol) at 0° C. then stirred at room temperature for 2 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, reaction mixture quenched with saturated NaHCO3 solution (100mL) and extracted with excess dichloromethane (2×150 mL). Combinedorganic layers were washed with brine solution (150 mL), dried overNa2SO4 and concentrated under reduced pressure to afford crude compound.Crude was purified through 100-200 combi-flash chromatography by eluting5% ethyl acetate in pet ether to afford tert-butyl4-(bromomethyl)-4-fluoroazepane-1-carboxylate 3 (1.7 g, 5.5 mmol, 61%yield) as a colorless oily liquid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 3.500-3.673 (m, 2H),3.434-3.477 (d, 2H), 3.162-3.269 (m, 4H), 1.980-2.114 (m, 4H),1.652-1.913 (m, 2H), 1.465 (s, 9H).

Synthesis of Tert-butyl 4-(azido methyl)-4-fluoroazepane-1-carboxylate(4)

To a stirred solution of tert-butyl 4-(bromomethyl)-4-fluoroazepane-1-carboxylate 3 (1.5 g, 4.854 mmol) in dimethylsulfoxide (20 mL) were added sodium azide (473 mg, 7.281 mmol) andsodium iodide (1 g, 7.281 mmol) then stirred at 130° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, to the reaction mixture added water (200 mL) and extractedwith ethyl acetate (2×150 mL). Combined organic layers were washed withbrine solution (200 mL), dried over sodium sulfate and concentratedunder reduced pressure to afford crude compound. Crude was purifiedthrough combi-flash chromatography by eluting 20% ethyl acetate in petether to afford tert-butyl 4-(azidomethyl)-4-fluoroazepane-1-carboxylate 4 (600 mg, 2.205 mmol, 45% yield)as a colorless oily liquid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 3.508-3.797 (m, 2H),3.148-3.387 (m, 4H), 1.952-2.158 (m, 3H), 1.648-1.790 (m, 2H), 1.442 (s,9H).

Synthesis of tert-butyl 4-(aminomethyl)-4-fluoroazepane-1-carboxylate(5)

A stirred solution of tert-butyl4-(azidomethyl)-4-fluoroazepane-1-carboxylate 5 (600 mg, 2.206 mmol) inmethanol (20 mL) was added 10% Pd/C (60 mg, 10% w/w) and then stirredunder balloon hydrogen atmosphere for 16 h. The progress of the reactionwas monitored by TLC. After completion of the reaction, reaction mixturefiltered through celite, washed the celite bed with 10% methanol indichloromethane (50 mL). Filtrate was concentrated under reducedpressure to afford crude compound. Crude was purified throughcombi-flash chromatography by eluting 30% ethyl acetate in pet ether toafford tert-butyl 4-(aminomethyl)-4-fluoroazepane-1-carboxylate 5 (400mg, 1.626 mmol, 74% yield) as a colorless oily liquid.

Analytical Data: 1HNMR (400 MHz, DMSO) δ 3.106-3.503 (m, 6H),2.618-2.625 (d, 2H), 2.570-2.576 (d, 1H), 1.490-1.912 (m, 6H), 1.380 (s,9H).

Synthesis of Tert-butyl 4-(((N-(tert-butoxycarbonyl) sulfamoyl) amino)methyl)-4-fluoroazepane-1-carboxylate (7)

To a stirred solution of tert-butyl4-(aminomethyl)-4-fluoroazepane-1-carboxylate 5 (400 mg, 1.626 mmol) indichloromethane (10 mL) were added diisopropylethylamine (315 mg, 2.439mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium6 (548 mg, 1.626 mmol) at 0° C. then stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After completionof the reaction, reaction mixture completely distilled off under reducedpressure to afford crude compound. Crude was purified through 100-200combi-flash chromatography by eluting 3% methanol in dichloromethane toafford tert-butyl 4-(((N-(tert-butoxycarbonyl) sulfamoyl) amino)methyl)-4-fluoroazepane-1-carboxylate 7 (350 mg, 0.823 mmol, 50% yield)as an brown solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 10.827 (s, 1H), 7.858 (bs,1H), 3.031-3.515 (m, 4H), 1.506-1.977 (m, 6H), 1.381 (s, 9H), 1.406 (s,9H), 1.218-1.234 (m, 1H).

Synthesis of Compound-8

A stirred solution of tert-butyl 4-(((N-(tert-butoxycarbonyl) sulfamoyl)amino) methyl)-4-fluoroazepane-1-carboxylate 7 (350 mg, 0.823 mmol) and4M HCl in dioxane (10 mL) was stirred at room temperature for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, organic solvents completely distilled off under reducedpressure to afford compound-8 (250 mg, 0.958 mmol, quantitative yield)as a brown gummy liquid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 9.088 (bs, 2H), 7.147 (t, 1H),6.880 (bs, 1H), 6.583 (bs, 1H), 2.994-3.151 (m, 6H), 2.077-2.163 (m,2H), 1.689-1.945 (m, 4H).

Synthesis of Compound 041

To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile9 (80 mg, 0.332 mmol) in N,N′-dimethylformamide (5 ml) were addedpotassium carbonate (137 mg, 0.996 mmol) and compound-8 (130 mg, 0.498mmol) then stirred at 90° C. for 6 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, added water (100 mL)and extracted with ethyl acetate (2×100 mL). Combined organic layerswere washed with brine solution (100 mL), dried over sodium sulfate andconcentrated under reduced pressure. Crude was purified throughpreparative HPLC method to afford Compound 041 (30 mg, 0.068 mmol, 21%yield) as an off white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.651 (s, 1H), 7.377 (s, 1H),7.319 (s, 1H), 6.860-6.895 (t, 1H), 6.567 (s, 2H), 3.945 (s, 3H), 3.937(s, 3H), 3.811-3.856 (m, 1H), 3.549-3.639 (m, 2H), 3.462-3.500 (m, 1H),3.073-3.3.137 (dd, 2H), 2.030-2.217 (m, 5H), 1.831-1.862 (bs, 1H).

Synthetic Scheme for Compounds 042 and 043

Step-1: Synthesis of tert-butyl 4-(benzyl amino) azepane-1-carboxylate(2)

To a stirred solution of tert-butyl 4-oxoazepane-1-carboxylate 1 (1 g,4.69 mmol) in DMF (7.5 mL) was added Benzyl amine (2.1 ml, 19.2 mmol)and STAB (2.1 g, 9.9 mmol) at 0° C. followed by AcOH (0.5 ml). Then thereaction mixture was allowed to stir at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of reaction, reactionmixture was directly poured on to ice cold water and stirred. Organicswere extracted with EtOAc thrice and combined organics were washed withbrine, dried and concentrated. Compound was directly absorbed on silicaand combi-flash chromatography to afford tert-butyl 4-(benzyl amino)azepane-1-carboxylate 2 (1.2 g, 3.947 mmol, 85% yield)

Analytical Data: LCMS: (M+H)+: m/Z: 305.2

Step-2: Synthesis of tert-butyl 4-aminoazepane-1-carboxylate (3)

To a stirred solution of tert-butyl 4-(benzyl amino)azepane-1-carboxylate 2 (1.1 g, 3.6 mmol) in MeOH (20 mL) was added Pd/C(100 mg) and stirred at RT for 16 h. After completion of reaction,reaction mixture was filtered through a pad of celite. The filtrate wasconcentrated under reduced pressure to afford light yellowish liquid oftert-butyl 4-aminoazepane-1-carboxylate 3 (600 mg, 2.803 mmol, 71%yield)

Analytical Data: 1H NMR (400 MHz, DMSO): 3.48-3.41 (m, 2H), 3.29-3.27(m, 1H), 3.10-3.05 (m, 1H), 2.97-2.94 (m, 1H), 1.93-1.89 (m, 1H),1.85-1.77 (m, 3H), 1.53-1.48 (m, 2H), 1.39 (s, 9H).

Step-3: tert-butyl4-((N-(tert-butoxycarbonyl)sulfamoyl)amino)azepane-1-carboxylate 5

To a stirred solution of tert-butyl 4-aminoazepane-1-carboxylate 3 (600mg, 2.8 mmol) in DCM (30 mL) was addedN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminiumchloride 4 (1.4 g, 3.08 mmol) slowly and then added DIPEA (1.5 ml, 8.4mmol) at same temperature. Then stirred the reaction mixture at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.Reaction mixture was directly absorbed on to silica, crude was purifiedthrough combi-flash chromatography by eluting 80% EtOAc in Hexane toafford tert-butyl4-((N-(tert-butoxycarbonyl)sulfamoyl)amino)azepane-1-carboxylate 5 (650mg, 1.65 mmol, 59% yield) as a white solid.

Analytical Data: 1H NMR (400 MHz, DMSO): 10.77 (s, 1H), 7.68-7.63 (m,1H), 3.32-3.30 (m, 1H), 3.20-3.10 (m, 4H), 1.89-1.74 (m, 3H), 1.58-1.48(m, 3H), 1.41-1.38 (m, 18H).

LCMS: (M−H)+: m/Z: 392.1

Step-4: Synthesis of 4-((N-sulfamoyl)amino)azepane-hydrochloride (6)

To a stirred solution of tert-butyl4-((N-(tert-butoxycarbonyl)sulfamoyl)amino)azepane-1-carboxylate 5 (650mg, 1.6 mmol) in dichloromethane (10 ml) was added 4M HCl in dioxane(0.6 mL) at 0° C. then stirred at room temperature for 16 h. Theprogress of the reaction was monitored by TLC. After completion ofreaction, organic solvents completely distilled off under reducedpressure. Crude compound was triturated with diethyl ether to give4-((N-sulfamoyl)amino)azepane-hydrochloride (310 mg) as white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ: 8.92 (brs, 2H), 6.72-6.70(brs, 1H), 6.53 (brs, 1H), 3.39-3.37 (s, 1H), 3.16-3.14 (m, 1H),3.16-3.14 (m, 1H), 3.08-3.05 (m, 1H), 3.05-2.98 (m, 2H), 2.06-2.04 (m,1H), 1.95-1.90 (m, 1H), 1.87-1.81 (m, 2H), 1.67-1.54 (m, 2H)

Step-5: Synthesis ofN-(1-(3-cyano-6,7-dimethoxyquinolin-4-yl)azepan-4-yl)sulfamoylamine(Compound 042)

To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile7 (146 mg, 0.65 mmol) in DMF (5 ml) was added4-((N-sulfamoyl)amino)azepane-hydrochloride (135 mg, 0.58 mmol) followedby K2CO3 (0.270 mg, 1.96 mmol) at RT. After addition, the reactionmixture was heated to 90° C. stirred for 16 h. The progress of thereaction was monitored by TLC. After completion of reaction, quenchedwith water and organics were extracted with EtOAc thrice and combinedorganics was washed with brine, dried and concentrate under reducedpressure to get crude. Crude compound was purified through prep-HPLC toaffordN-(1-(3-cyano-6,7-dimethoxyquinolin-4-yl)azepan-4-yl)sulfamoylamine(Compound 042) (22 mg, 0.054 mmol, 9% yield) was obtained as a paleyellow fluffy solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ: 8.62 (s, 1H), 7.36 (s, 1H),7.32 (s, 1H), 6.72 (d, 1H), 6.51 (s, 2H), 3.94 (s, 6H), 3.62-3.61 (m,3H), 3.54-3.51 (m, 2H), 2.21-2.10 (m, 2H), 1.93-1.91 (m, 1H), 1.87-1.74(m, 3H)

LCMS: (M+H)⁺: m/Z: 406.31

Step-6: Synthesis of N-(1-(6, 7-dimethoxyquinazolin-4-yl)azepan-4-yl)sulfamoylamine (Compound 043)

To a stirred solution of 4-chloro-6, 7-dimethoxyquinazoline 8 (146 mg,0.65 mmol) in DMF (5 ml) was added 4-((N-sulfamoyl) amino)azepane-hydrochloride (135 mg, 0.589 mmol) followed by K2CO3 (0.270 mg,1.96 mmol) at RT. After addition, the reaction mixture was heated to 90°C. stirred for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, reaction mixture was poured on waterand extracted with EtOAc thrice and combined organic layer was washedwith brine, dried under reduced pressure to get crude. Crude compoundwas purified through prep-HPLC to afford N-(1-(6,7-dimethoxyquinazolin-4-yl)azepan-4-yl) sulfamoylamine Compound 043 (24mg, 0.062 mmol, 9.6% yield) was obtained as an off-white solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ: 8.36 (s, 1H), 7.27 (s, 1H),7.13 (s, 1H), 6.62 (d, 1H), 6.49 (s, 2H), 3.87-3.96 (m, 8H), 3.63-3.71(m, 2H), 3.31-3.37 (m, 1H), 2.2-2.25 (m, 1H), 1.95-2.01 (m, 3H),1.82-1.85 (m, 1H), 1.50-1.58 (m, 1H)

LCMS: (M+H)⁺: m/Z: 382.19

Synthetic Scheme of Compounds 044 and 045

Step-1: Synthesis of tert-butyl4-(((trifluoromethyl)sulfonyl)oxy)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate(2)

To a solution of tert-butyl 4-oxoazepane-1-carboxylate (1.5 g, 7.04mmol, 1 eq.) in THF (20 mL) at −78° C., was added a IN solution ofLiHMDS (7.7 mL, 7.74 mmol) dropwise under nitrogen. The mixture wasstirred for 20 minutes, then a solution of PhNTf2 (2.75 g, 7.71 mmol) inTHF (10 mL) was added. The mixture was warmed to 0° C. and stirred for 3hours. The reaction was concentrated and diluted with DCM, filteredthrough neutral alumina and the product was eluted with 9:1Hexanes/EtOAc to afford tert-butyl4-(((trifluoromethyl)sulfonyl)oxy)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate(2.1 g, 6.08 mmol, 87% yield).

Analytical Data: 1H NMR (400 MHz, CDCl3): 5.90 (m, 1H), 3.90-3.99 (m,2H), 3.51-3.60 (m, 2H), 2.56 (m, 1H), 1.92-1.97 (m, 2H), 1.45 (s, 9H)

Step-2: Synthesis of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate(4)

To a stirred solution of tert-butyl4-(((trifluoromethyl)sulfonyl)oxy)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate2 (1.5 g, 4.34 mmol) in dioxane was added bis(pinacolato)diboron 3 (1.3g, 4.9 mmol) and potassium acetate (1.28 g, 12.9 mmol) at RT. Themixture was degassed under nitrogen for 15 minutes, then addedPdCl2(PPh3)2 (300 mg, 0.43 mmol) at RT and the mixture was degassed foran additional 5 minutes. The reaction was stirred at 80° C. overnight,concentrated, diluted with ethyl acetate and filtered through celitepad, filtrate was concentrated under reduced pressure to get crude (3gm) was used as such for the next step.

Step-3: tert-butyl4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate(5)

To the stirred solution of 4-chloro-6,7-dimethoxyquinazoline (208 mg,0.9 mmol) in Dioxane (7 mL) and water (1 ml) was added tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate4 (600 mg crude, 1.8 mmol) followed by Na2CO3 (300 mg, 2.7 mmol) anddegassed with Argon for 30 min. Then added PdCl2(dppf).DCM (76 mg, 0.09mmol) was added and purged again for 5 min with Argon. The reactionmixture was heated to 80° C. for 16 h. The progress of the reaction wasmonitored by TLC. Reaction mixture was filtered through celite pad andfiltrate was quenched with water and extracted with EtOAc thrice andcombined organic layer was washed with brine & water. Organic layer wasconcentrated under reduced pressure to get crude. Crude compound waspurified through combi-flash chromatography by eluting 90% EtOAc inHexane to afford tert-butyl4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate5 (250 mg, 0.649 mmol, 70% yield) as a Light brown solid.

Analytical Data: 1H NMR (400 MHz, DMSO): 9.06 (s, 1H), 7.55 (s, 1H),7.30-7.30 (m, 1H), 6.19 (t, 1H), 4.11-4.44 (m, 2H), 4.00-4.05 (m, 6H),3.69-3.74 (m, 2H), 2.81-2.83 (m, 2H), 2.07-2.10 (m, 2H), 1.48 (s, 9H)

LCMS: (M−H)⁺: m/Z: 386.2

Step-4: 6,7-dimethoxy-4-(2,3,6,7-tetrahydro-1H-azepin-4-yl)quinazolinehydrochloride (6)

To the stirred solution of tert-butyl4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate5 (100 mg, 0.83 mmol) in 1,4 Dioxane (10 mL) was added 4.0M HCl in1,4-Dioxane (1 ml) slowly at 0° C. and slowly allowed to RT and stirredfor 2 h. After completion of reaction, volatile organics were removedunder reduced pressure, co-distilled thrice with DCM and triturated withether to give off-white solid6,7-dimethoxy-4-(2,3,6,7-tetrahydro-1H-azepin-4-yl)quinazolinehydrochloride 6 (88 mg, 0.24 mmol, 95% yield)

Analytical Data: LCMS: (M−H)+: m/Z: 286.2

Step-5: tert-butyl((4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-azepin-1-yl)sulfonyl)carbamate (8)

To the stirred solution of6,7-dimethoxy-4-(2,3,6,7-tetrahydro-1H-azepin-4-yl)quinazolinehydrochloride 6 (90 mg, 0.28 mmol) in DCM was addedN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminiumchloride 4 (95 mg, 0.28 mmol) and DIPEA (0.146 ml, 0.841 mmol) at roomtemperature. Then stirred the reaction mixture at room temperature for16 h. The progress of the reaction was monitored by TLC. Reactionmixture was directly absorbed on to silica and converted into slurry.Crude was purified through combi-flash chromatography by eluting 90%EtOAc in Hexane to afford tert-butyl((4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-azepin-1-yl)sulfonyl)carbamate8 (120 mg, 0258 mmol, 92% yield) as an off-white solid.

Analytical Data: 1H NMR (400 MHz, DMSO): 11.03 (s, 1H), 8.98 (s, 1H),7.47 (s, 1H), 7.34 (s, 1H), 6.15 (t, 1H), 4.17-4.16 (m, 2H), 3.96 (s,3H), 3.90 (s, 3H), 3.57 (t, 2H), 2.78-2.80 (m, 2H), 2.01-2.03 (m, 2H),1.38 (s, 9H)

LCMS: (M−H)⁺: m/Z: 465.2

Step-6: Synthesis of4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-azepine-1-sulfonamide(Compound 044)

To a stirred solution of tert-butyl((4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-azepin-1-yl)sulfonyl)carbamate8 (125 mg, 0.26 mmol) in dichloromethane (5 ml) was added was added TFA(1.2 mL) at 0° C., then stirred at same temperature for 4 h. Theprogress of the reaction was monitored by TLC. After completion ofreaction, TFA was neutralized by using aq.NaHCO3, and extracted with 10%MeOH/DCM and dried and concentrated under reduced pressure to get crude.Crude compound was submitted to prep-HPLC to afford4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-azepine-1-sulfonamideCompound 044 (70 mg, 0.192 mmol, 70% yield) as an off-white solid.

Analytical Data: 1H NMR (400 MHz, DMSO): 8.97 (s, 1H), 7.52 (s, 1H),7.32 (s, 1H), 6.82 (s, 2H), 6.16 (t, 1H), 4.02-4.00 (m, 2H), 3.96 (s,3H), 3.98 (s, 6H), 3.51 (t, 2H), 2.82-2.79 (m, 2H), 2.02-1.98 (m, 2H)

LCMS: (M−H)⁺: m/Z: 365.1

Step-7: tert-butyl((4-(6,7-dimethoxyquinazolin-4-yl)azepan-1-yl)sulfonyl)carbamate (9)

To a stirred solution of tert-butyl((4-(6,7-dimethoxyquinazolin-4-yl)-2,3,6,7-tetrahydro-1H-azepin-1-yl)sulfonyl)carbamate8 (250 mg, 0.53 mmol) in MeOH (3 mL) was added 10% Pd/C (25 mg) andstirred at RT for 16 h. After completion of reaction, reaction mixturewas filtered through a celite pad. Filtrate was concentrated underreduced pressure to give light yellowish liquid of tert-butyl((4-(6,7-dimethoxyquinazolin-4-yl)azepan-1-yl)sulfonyl)carbamate 9 (220mg, 0.472 mmol, 87% yield)

Analytical Data: 1HNMR (400 MHz, DMSO) δ: 11.13 (s, 1H), 8.96 (s, 1H),7.45 (s, 1H), 7.32 (s, 1H), 6.97 (d, 2H), 3.96-3.95 (m, 6H), 3.89-3.81(m, 1H), 3.79-3.64 (m, 1H), 3.58-3.32 (m, 3H), 2.04-1.85 (m, 6H).

LCMS: (M+H)⁺: m/Z: 467.11

Step-8: Synthesis of 4-(6,7-dimethoxyquinazolin-4-yl)azepane-1-sulfonamide hydrochloride (Compound045)

To a stirred solution of tert-butyl((4-(6,7-dimethoxyquinazolin-4-yl)azepan-1-yl)sulfonyl)carbamate 9 (250mg, 0.53 mmol) in dichloromethane (2.5 mL) was added 4M HCl in dioxane(2.5 mL) at 0° C. then stirred at room temperature for 16 h. Theprogress of the reaction was monitored by TLC. Crude reaction mixturewas purified through prep-HPLC to afford4-(6,7-dimethoxyquinazolin-4-yl)azepane-1-sulfonamide hydrochlorideCompound 045 (25 mg, 0.062 mmol, 11% yield) was obtained as an off-whitesolid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ: 8.96 (s, 1H), 7.44 (s, 1H),7.32 (s, 1H), 6.71 (s, 2H), 3.95-3.96 (m, 6H), 3.81-3.83 (m, 1H),3.47-3.53 (m, 2H), 3.17-3.23 (m, 1H), 2.00-2.04 (m, 2H), 1.85-1.95 (m,4H)

LCMS: (M+H)⁺: m/Z: 367.3

Example 9: N-((5-(6, 7-dimethoxyquinazolin-4-yl) pyridin-2-yl) methyl)sulfamide Step-1: 5-(6, 7-dimethoxyquinazolin-4-yl) picolinonitrile

In a sealed tube, to the stirred solution of4-chloro-6,7-dimethoxyquinazoline 1 (1.5 g, 6.67 mmol) in dioxane (50mL) and water (20 mL) were added (6-cyanopyridin-3-yl)boronic acid (1.08g, 0.72 mmol) and sodium carbonate (2.12 g, 20.0 mmol) was then degassedthe reaction mixture for 30 minutes. Then, [1, 1′-Bis(diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethanecomplex (544 mg, 0.66 mmol) was added again degassed for 5 minutes andstirred the reaction mixture at 100° C. for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction,reaction mixture was poured into water (100 mL) and filtered throughcelite. Washed the celite bed with 10% methanol in dichloromethane (100mL) and separated the two layers. Organic layer washed with brinesolution (200 mL), dried over sodium sulfate and concentrated underreduced pressure. Crude was purified using combi-flash columnchromatography by eluting 3% methanol in dichloromethane to afford 5-(6,7-dimethoxyquinazolin-4-yl) picolinonitrile 2 (700 mg, 2.39 mmol, 37%)as a brown solid.

Analytical Data: 1H NMR (400 MHz, DMSO) 9.18 (d, 2H), 8.51 (d, 1H), 8.27(d, 1H), 7.48 (s, 1H), 7.23 (s, 1H), 4.01 (s, 3H), 3.86 (s, 3H). LCMS:(M+H+): m/Z: 292.9

Step-2: (5-(6, 7-dimethoxyquinazolin-4-yl) pyridin-2-yl) methanamine

To a stirred solution of 5-(6, 7-dimethoxyquinazolin-4-yl)picolinonitrile 2 (500 mg, 1.7 mmol) in acetic acid (30 mL) was added10% Pd/C (300 mg) and stirred under balloon hydrogen atmosphere at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, reaction mixture was passed throughcelite and washed the celite bed with 5% methanol in dichloromethane(100 mL). Filtrate was concentrated under reduced pressure to afforded(5-(6, 7-dimethoxyquinazolin-4-yl) pyridin-2-yl) methanamine 3 (500 mg,1.689 mmol, 98% yield) as a yellow solid.

Analytical Data: 1H NMR (400 MHz, DMSO) 9.15 (s, 1H), 8.97 (s, 1H), 8.29(d, 1H), 7.70 (d, 1H), 7.45 (s, 1H), 7.25 (s, 1H), 4.11 (brs, 2H), 4.00(s, 3H), 3.87 (s, 3H). LCMS: (M+H+): m/Z: 297.0

Step-3: Tert-butyl (N-((5-(6, 7-dimethoxyquinazolin-4-yl) pyridin-2-yl)methyl) sulfamoyl) carbamate (Int-5)

To a stirred solution of (5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)methanamine 3 (500 mg, 1.689 mmol) in dichloromethane (40 ml) were addeddiisopropylethylamine (1.65 mL, 10.134 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminiumchloride 4 (569 mg, 1.689 mmol) at RT allowed to stir at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, organic solvents completely distilledoff under reduced pressure to afford crude compound. Crude compound waspurified over combi flash column chromatography by eluting 2% methanolin dichloromethane to afforded tert-butyl (N-((5-(6,7-dimethoxyquinazolin-4-yl) pyridin-2-yl) methyl) sulfamoyl) carbamate(300 mg, 0.631 mmol, 37% yield) as a yellow solid.

Analytical Data: 1H NMR (400 MHz, DMSO) 9.15 (s, 1H), 8.37 (s, 1H), 8.29(d, 1H), 7.67 (d, 1H), 7.46 (s, 1H), 7.26 (s, 1H), 4.37 (d, 2H), 4.01(s, 3H), 3.59 (s, 3H), 1.39 (s, 9H).

LCMS: (M+H+): m/Z: 475.9

Step-4: N-((5-(6, 7-dimethoxyquinazolin-4-yl) pyridin-2-yl) methyl)sulfamide (Compound 047)

To a stirred solution of tert-butyl(N-((5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)methyl)sulfamoyl)carbamateInt-5 (100 mg, 0.210 mmol) in 1,4-dioxane (1.0 ml) was added 4M HCl indioxane (2.5 mL) at RT, then stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, organicsolvents completely distilled off under reduced pressure to afford crudecompound. Crude compound was purified through prep. HPLC to afford purecompound of N-((5-(6, 7-dimethoxyquinazolin-4-yl) pyridin-2-yl) methyl)sulfamide 30 mg, 0.08 mmol, 38% yield) (Compound 47) as an off whitesolid.

Analytical Data: 1H NMR (400 MHz, DMSO) 9.15 (s, 1H), 8.93 (s, 1H), 8.28(d, 1H), 7.73 (d, 1H), 7.46 (s, 1H), 7.30-7.27 (m, 2H), 6.75 (s, 2H),4.32 (d, 2H), 4.01 (s, 3H), 3.85 (s, 3H). LCMS: (M+H+): m/Z: 375.9; M.W.411.86.

Synthetic Scheme for Compound 046

Synthesis of Tert-butyl((5-(3-cyano-6,7-dimethoxyquinolin-4-yl)pyridin-2-yl)methyl)carbamate(2)

To a stirred solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile(500 mg, 2.01 mmol) in 3:1 dioxane:H₂O (20 mL) were added Na₂CO₃ (641mg, 6.04 mmol) and tert-butyl((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamateInt-9 (1.3 g, 4.03 mmol) at RT, was then degassed the reaction mixturefor 30 minutes. Then[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (165 mg,0.2 mmol) was added again degassed for 5 minutes and stirred thereaction mixture at 100° C. for 16 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, reaction mixture waspoured into water (100 mL) and filtered through celite. Washed thecelite bed with 10% methanol in dichloromethane (100 mL) and separatedthe two layers. Organic layer washed with brine solution (200 mL), driedover sodium sulfate and concentrated under reduced pressure. Crude waspurified prep HPLC method to afford tert-butyl((5-(3-cyano-6,7-dimethoxyquinolin-4-yl)pyridin-2-yl)methyl)carbamate(2) (250 mg, 0.127 mmol, 30%) as a yellow solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 9.066 (s, 1H), 8.72 (s, 1H),8.07-8.09 (dd, 1H), 7.52-7.59 (m, 4H), 6.86 (s, 1H), 4.38-4.41 (m, 2H),4.01 (s, 3H), 3.74 (s, 3H), 1.43 (s, 9H).

LCMS: (M+H⁺): m/Z: 421.2

Synthesis of4-(6-(aminomethyl)pyridin-3-yl)-6,7-dimethoxyquinoline-3-carbonitrile(3)

To a stirred solution of tert-butyl((5-(3-cyano-6,7-dimethoxyquinolin-4-yl)pyridin-2-yl)methyl)carbamate 2(250 mg, 0.127 mmol) in dioxane (2 mL) was added 4M HCl in dioxane (4mL) at 0° C. then stirred at room temperature for 6 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction,organic solvents completely distilled off under reduced pressure. To thecrude residue was washed with ether to afford4-(6-(aminomethyl)pyridin-3-yl)-6,7-dimethoxyquinoline-3-carbonitrile(3) (150 mg, 0.451 mmol, 88% yield) as a pale brown solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 9.1 (s, 1H), 8.89 (s, 1H),8.45 (brs, 2H), 8.19-8.22 (dd, 1H), 7.76-7.79 (dd, 1H), 7.61 (s, 1H),6.82 (s, 1H), 4.39-4.41 (m, 2H), 4.02 (s, 3H), 3.74 (s, 3H).

LCMS: (M+H⁺): m/Z: 321.1

Synthesis of tert-butyl(N-((5-(3-cyano-6,7-dimethoxyquinolin-4-yl)pyridin-2-yl)methyl)sulfamoyl)carbamate(5)

To a stirred solution of4-(6-(aminomethyl)pyridin-3-yl)-6,7-dimethoxyquinoline-3-carbonitrile(3) (200 mg, 0.625 mmol) in dichloromethane (4 mL) were addeddiisopropylethylamine (0.326 mL, 1.87 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium4 (210 mg, 0.625 mmol) at RT, then stirred at room temperature for 16 h.The progress of the reaction was monitored by TLC. After completion ofthe reaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified combiflash column chromatography by eluting 60% ethyl acetate in pet-ether toafford tert-butyl(N-((5-(3-cyano-6,7-dimethoxyquinolin-4-yl)pyridin-2-yl)methyl)sulfamoyl)carbamate(5) (150 mg, 0.30 mmol, 48% yield) as a yellow solid.

LCMS: (M+H)⁺: m/Z: 499.97

Preparation of Compound 046

To a stirred solution of tert-butyl(N-((5-(3-cyano-6,7-dimethoxyquinolin-4-yl)pyridin-2-yl)methyl)sulfamoyl)carbamate(5) (150 mg, 0.294 mmol) in 1,4-dioxane (1.0 mL) was added 4M HCl indioxane (2.0 mL) at RT. Reaction mixture was stirred at RT for 16 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, organic solvents completely distilled off under reducedpressure to afford crude compound. Crude compound was purified throughprep HPLC method to afford pure compound of Compound 046 (85 mg, 0.213mmol, 66% yield) as an Off-white solid.

Analytical Data: ¹H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 8.71-8.72 (d,1H), 8.08-8.11 (dd, 1H), 7.76-7.78 (dd, 1H), 7.58 (s, 1H), 7.29-7.31 (t,1H), 6.85 (s, 1H), 6.77 (s, 1H), 4.35 (d, 2H), 4.0 (s, 3H), 3.73 (s,3H).

LCMS: (M+H)⁺: m/Z: 400.0

Synthesis of tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate (6)

To a stirred solution of (5-bromopyridin-2-yl)methanamine 6 (1 g, 5.34mmol) in dichloromethane (20 mL) was added diisopropylethylamine (2.8mL, 16.04 mmol), and di-tert-butyl dicarbonate (1.28 mL, 5.88 mmol) at0° C. Then stirred the reaction mixture at room temperature for 16 h.The progress of the reaction was monitored by TLC. After completion,reaction mixture was poured into ice cold water (500 mL) and extractedwith DCM (2×100 mL). Combined organic layers were washed with brinesolution (200 mL), dried over sodium sulfate and concentrated underreduced pressure to afford tert-butyl((5-bromopyridin-2-yl)methyl)carbamate 6 (1.0 g, 3.49 mmol, 66% yield)as a brown solid.

Analytical Data: ¹H NMR (400 MHz, CDCl₃) δ 8.6 (d, 1H), 8.00-8.03 (dd,1H), 7.45 (t, 1H), 7.23 (d, 1H), 4.17 (d, 1H), 1.39 (s, 9H).

LCMS: (M−Boc)⁺: m/Z: 287.0

Preparation of Intermediate-9

To a stirred solution of tert-butyl((5-bromopyridin-2-yl)methyl)carbamate 6 (1 g, 3.49 mmol) in dioxane (15ml) was added KOAc (1.02 g, 10.48 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.77 g,6.99 mmol) at RT, was then degassed the reaction mixture for 30 minutes.Then [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (285mg, 0.34 mmol) was added again degassed for 5 minutes and stirred thereaction mixture at 100° C. for 16 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, reaction mixture waspoured into water (100 mL) and filtered through celite. Washed thecelite bed with ethyl acetate (100 mL) and separated the two layers.Organic layer washed with brine solution (200 mL), dried over sodiumsulfate and concentrated under reduced pressure. Crude was use aswithout purification as such as next step to afford Int-9 (1.1 g, crude)as a white solid.

Example 10: (N-(2-((5-(6, 7-dimethoxyquinazolin-4-yl) pyridin-2-yl)amino) ethyl) sulfamide hydrochloride salt Step-1: 5-(6,7-dimethoxyquinazolin-4-yl) pyridin-2-ol

To a stirred solution of 4-chloro-6, 7-dimethoxyquinazoline 1 (107 mg,0.48 mmol) in dioxane (7 mL) and water (3 mL) were added(6-hydroxypyridin-3-yl) boronic acid 2 (100 mg, 0.72 mmol) and sodiumcarbonate (0.15 g, 1.44 mmol). Reaction mixture was then degassed for 30minutes. Then chloro [1, 1′-Bis (diphenylphosphino) ferrocene]dichloropalladium (II) dichloromethane complex (38 mg, 0.048 mmol) wasadded, degassed again the reaction mixture for 5 minutes and stirred thereaction mixture at 110° C. for 16 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, reaction mixture waspoured into water (100 mL) and filtered through celite. Washed thecelite bed with 10% methanol in dichloromethane (100 mL) and separatedthe two layers. Organic layer washed with brine solution (100 mL), driedover sodium sulfate and concentrated under reduced pressure. Crude waspurified through 100-200 silica gel column chromatography by eluting100% ethyl acetate to afford 5-(6, 7-dimethoxyquinazolin-4-yl)pyridin-2-ol 3 (57 mg, 0.201 mmol, 45%) as a yellow solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 11.98 (brs, 1H), 9.02 (s, 1H),7.97 (s, 1H), 7.35 (s, 1H), 7.38 (d, 2H), 6.52 (d, 1H), 3.90 (s, 3H),3.98 (s, 3H). LCMS: (M+H+): m/Z: 283.9

Step-2: 4-(6-chloropyridin-3-yl)-6, 7-dimethoxyquinazoline

A solution of 5-(6, 7-dimethoxyquinazolin-4-yl) pyridin-2-ol 3 (500 mg,1.766 mmol) and phosphorous oxychloride (16 mL) was stirred at 110° C.for 2 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, reaction mixture was poured into saturatedNaHCO3 solution (100 mL) slowly under cooling and extracted with 5%methanol in dichloromethane (2×50 mL). Combined organic layers werewashed with brine solution (100 mL), dried over sodium sulfate andconcentrated under reduced pressure to afford4-(6-chloropyridin-3-yl)-6,7-dimethoxyquinazoline 4 (430 mg, 0.305 mmol,86%) as an off white solid.

Analytical Data: LCMS: (M+H+): m/Z: 301.9

Step-3: N1-(5-(6, 7-dimethoxyquinazolin-4-yl) pyridin-2-yl)ethane-1,2-diamine

A solution of 4-(6-chloropyridin-3-yl)-6, 7-dimethoxyquinazoline 4 (300mg, 0.996 mmol) and ethylenediamine (5 mL) was stirred at 100° C. for 5h. The progress of the reaction was monitored by TLC. After completionof the reaction, to the reaction mixture completely distilled off underreduced pressure to afford crude compound. Crude compound was purifiedthrough combi-flash chromatography by eluting 10% methanol indichloromethane to afford pure compound of N1-(5-(6,7-dimethoxyquinazolin-4-yl) pyridin-2-yl) ethane-1, 2-diamine 5 (130 mg,0.4 mmol, 40% yield) as a pale brown solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 9.01 (s, 1H), 8.51 (s, 1H),7.91 (d, 1H), 7.37 (s, 1H), 7.38 (s, 1H), 6.65 (d, 1H), 3.87 (s, 3H),3.98 (s, 3H), 2.69-2.72 (m, 4H). LCMS: (M+H+): m/Z: 326.0

Step-4: Tert-butyl (N-(2-((5-(6, 7-dimethoxyquinazolin-4-yl)pyridin-2-yl) amino) ethyl) sulfamoyl) carbamate

To a stirred solution ofN1-(5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)ethane-1,2-diamine 5(100 mg, 0.307 mmol) in dichloromethane (8 ml) were addeddiisopropylethylamine (0.1 mL, 0.461 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminiumchloride 6 (156 mg, 0.461 mmol) at 0° C. then stirred at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, reaction mixture completely distilledoff under reduced pressure to afford crude compound. Crude was purifiedthrough 100-200 silica gel column chromatography by eluting 3% methanolin dichloromethane to afford tert-butyl (N-(2-((5-(6,7-dimethoxyquinazolin-4-yl) pyridin-2-yl) amino) ethyl) sulfamoyl)carbamate 7 (140 mg, 0.277 mmol, 90% yield) as a pale yellow solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 10.92 (bs, 1H), 9.02 (s, 1H),8.52 (s, 1H), 7.94 (d, 1H), 7.70 (t, 1H), 7.38 (s, 2H), 7.19 (t, 1H),6.65 (d, 1H), 3.87 (s, 3H), 3.98 (s, 3H), 3.48-3.46 (m, 2H), 3.09-3.08(m, 2H), 1.38 (s, 9H). LCMS: (M+H+): m/Z: 504.9

Step-5: (N-(2-((5-(6, 7-dimethoxyquinazolin-4-yl) pyridin-2-yl) amino)ethyl) sulfamide hydrochloride Salt (Compound 048)

To a stirred solution of tert-butyl(N-(2-((5-(6,7-dimethoxyquinazolin-4-yl)pyridin-2-yl)amino)ethyl)sulfamoyl)carbamate7 (110 mg, 0.216 mmol) in dioxane (2 ml) was added 4M HCl in dioxane (8mL) at 0° C. then stirred at room temperature for 6 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction,organic solvents completely distilled off under reduced pressure. Crudewas purified through prep HPLC method to afford (N-(2-((5-(6,7-dimethoxyquinazolin-4-yl) pyridin-2-yl) amino) ethyl) sulfamidehydrochloride salt (Compound 048).

(41 mg, 0.101 mmol, 46% yield) as a yellow solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.53 (s, 1H),7.94 (d, 1H), 7.38 (s, 2H), 7.18-7.10 (m, 1H), 6.67-6.63 (m, 2H), 6.57(s, 2H), 3.98 (s, 3H), 3.88 (s, 3H), 3.48-3.51 (m, 2H), 3.11-3.06 (m,2H). LCMS: (M+H+): m/Z: 405.1

Compound 050 was prepared based on the general procedure of Example 10.

(400 MHz, DMSO) δ 8.94 (s, 1H), 7.43 (s, 1H), 7.31 (s, 1H), 6.44 (s,3H), 3.96 (d, 6H), 3.18 (t, 2H), 2.85 (dd, 2H), 1.85-1.73 (m, 2H),1.56-1.46 (m, 2H), 1.42 (d, 2H). LCMS 355.1. MW 390.88

Example 11: N-(5-(6, 7-dimethoxyquinazolin-4-yl) pentyl) sulfamideStep-1: (E)-5-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pent-4-enenitrile

In a sealed tube, to a stirred solution of pent-4-ynenitrile 1 (500 mg,6.329 mmol) in octane (7 mL) were added pinacol borane (2.4 g, 18.987mmol) and 4-(dimethyl amino)benzoic acid (52 mg, 0.316 mmol) thenstirred the reaction mixture at 100° C. for 16 h. The progress of thereaction was monitored by TLC. After completion, reaction mixture wasfiltered and the filtrate was concentrated under reduced pressure toafford crude compound of (E)-5-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) pent-4-enenitrile 2 (600 mg, crude) as a colorlessgummy solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 7.93 (s, 1H), 6.47 (dt, 1H),5.45 (d, 1H), 2.66-2.56 (t, 2H), 2.36 (m, 2H), 1.20 (s, 13H).

Structure 1HNMR

1H NMR (400 MHz, DMSO): δ 7.93 (s, 1H), 6.49-6.43 (m, 1H), 5.36 (d, 1H),2.49-2.44 (m, 2H), 2.21-2.16 (m, 2H), 1.69-1.66 (m, 2H), 1.18 (s, 12H).

Step-2: Potassium (E)-(4-cyanobut-1-en-1-yl) trifluoroborate

To a stirred solution of (E)-5-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) pent-4-enenitrile 2 (600 mg, 2.898 mmol) inmethanol (6 mL) and water (6 mL) was added potassium hydrogen fluoride(1.35 g, 17.391 mmol) and stirred the reaction mixture at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion of the reaction, reaction mixture completely distilledoff under reduced pressure, to the crude residue was added acetone (10mL) and unwanted solids were filtered off. Filtrate was concentratedunder reduced pressured to afford crude compound. Crude was purified bytrituration with diethyl ether (50 mL) to afford potassium(E)-(4-cyanobut-1-en-1-yl) trifluoroborate 3 (200 mg, crude) as an offwhite solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 5.47 (dt, 1H), 5.34 (ds, 1H),2.43 (t, 2H), 2.13 (d, 2H).

Step-3: (E)-5-(6, 7-dimethoxyquinazolin-4-yl) pent-4-enenitrile

To a stirred solution of 4-chloro-6, 7-dimethoxyquinazoline 4 (200 mg,0.893 mmol) in tetrahydrofuran (2.2 mL) and water (1.5 mL) were addedpotassium (E)-(4-cyanobut-1-en-1-yl) trifluoroborate 3 (183 mg, 0.982mmol) and potassium phosphate (946 mg, 4.465 mmol) then degassed thereaction mixture for 30 minutes. Then added chloro(2-dicyclohexylphosphino-2′, 4′, 6′-triisopropyl-1, 1′-biphenyl)[2-(2′-amino-1, 1′-biphenyl)] palladium (II) (35 mg, 0.044 mmol) againdegassed the reaction mixture for 5 minutes and stirred the reactionmixture at 50° C. for 16 h. The progress of the reaction was monitoredby TLC. After completion of the reaction, reaction mixture was pouredinto water (100 mL) and filtered through celite. Washed the celite bedwith 10% methanol in dichloromethane (100 mL) and separated the twolayers. Organic layer washed with brine solution (100 mL), dried oversodium sulfate and concentrated under reduced pressure. Crude waspurified through 100-200 silica gel column chromatography by eluting 2%methanol in dichloromethane to afford (E)-5-(6,7-dimethoxyquinazolin-4-yl) pent-4-enenitrile 5 (150 mg, 0.557 mmol,62%) as a brown solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.97 (s, 1H), 7.61 (d, 2H),7.32-7.22 (m, 2H), 3.98 (d, 6H), 2.83 (t, 2H), 2.72-2.63 (m, 2H).

Same reaction was performed with corresponding pinacol boronate toobtain the following intermediate

Structure 1HNMR

1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 7.62 (s, 1H), 7.55-7.51 (d, 1H),7.29 (s, 1H), 7.28-7.26 (m, 1H), 3.98- 3.96 (m, 6H), 3.89-3.82 (m, 2H),2.55-2.60 (t, 2H), 1.89-1.82 (m, 2H). MS 284.2

Step-4: 5-(6, 7-dimethoxyquinazolin-4-yl) pentan-1-amine

To a stirred solution of(E)-5-(6,7-dimethoxyquinazolin-4-yl)pent-4-enenitrile 5 (670 mg, 2.49mmol) in 1,4-dioxane (25 mL) and water (10 ml) were added lithiumhydroxide monohydrate (230 mg, 5.48 mmol), Raney Ni (700 mg) and 10%Pd/C (220 mg) and stirred the reaction mixture under balloon hydrogenatmosphere at room temperature for 16 h. The progress of the reactionwas monitored by TLC. After completion of the reaction, reaction mixturefiltered through celite and washed the celite bed with 5% methanol indichloromethane (100 mL). Filtrate was concentrated under reducedpressure. Crude compound was purified through Grace reverse phase methodby eluting 40% acetonitrile in 0.1% formic acid in water to afford 5-(6,7-dimethoxyquinazolin-4-yl) pentan-1-amine 4 (200 mg, 0.727 mmol, 29%yield) as a reddish brown gummy liquid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.46 (s, 1H),7.43 (s, 1H), 7.31 (s, 1H), 3.95 (s, 7H), 3.23-3.17 (t, 2H), 2.64 (t,2H), 1.79 (m, 2H), 1.51 (m, 2H), 1.40 (m, 2H).

Structure 1HNMR

1HNMR (400 MHz, DMSO) δ 8.93 (s, 1H), 7.43 (s, 1H), 7.31 (s, 1H), 3.95(s, 6H), 3.20-3.6 (m, 2H), 1.81-1.77 (m, 2H), 1.34 (m, 6H). MS 290.3

Step-5: Tert-butyl (N-(5-(6, 7-dimethoxyquinazolin-4-yl) pentyl)sulfamoyl) carbamate

To a stirred solution of 5-(6,7-dimethoxyquinazolin-4-yl)pentan-1-amine6 (200 mg, 0.727 mmol) in dichloromethane (5 ml) were addeddiisopropylethylamine (140 mg, 1.091 mmol) andN-(1-(N-(tert-butoxycarbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium7 (269 mg, 0.8 mmol) at 0° C. then stirred at room temperature for 16 h.The progress of the reaction was monitored by TLC. After completion, tothe reaction mixture added water (50 mL) and extracted withdichloromethane (2×50 mL). Combined organic layers were washed withbrine solution (50 mL), dried over sodium sulfate and concentrated underreduced pressure to afford crude compound. Crude was purified through100-200 silica gel column chromatography by eluting 2% methanol indichloromethane to afford tert-butyl (N-(5-(6,7-dimethoxyquinazolin-4-yl) pentyl) sulfamoyl) carbamate (200 mg, 0.44mmol, 60% yield) as a pale brown solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 10.76 (s, 1H), 8.93 (s, 1H),7.53 (bs, 1H), 7.42 (s, 1H), 7.31 (s, 1H), 3.96 (s, 6H), 3.18 (t, 2H),2.89-2.81 (m, 2H), 1.83-1.72 (m, 2H), 1.51 (m, 2H). 1.39 (m. 11H),

Structure 1HNMR

1H NMR (400 MHz, DMSO) δ 10.76 (bs, 1H), 8.93 (s, 1H), 7.50-7.53 (m,1H), 7.43 (s, 1H), 7.31 (s, 1H), 3.96 (s, 6H), 3.16-3.20 (m, 2H),2.84-2.87 (m, 2H), 1.76-1.80 (m, 2H), 1.41-1.45 (m, 2H), 1.38 (s, 9H),1.32-1.34 (m, 2H), 1.14-1.22 (m, 2H). MS 469.15

Step-6: N-(5-(6, 7-dimethoxyquinazolin-4-yl) pentyl) sulfamide (Compound051)

To a stirred solution of tert-butyl(N-(5-(6,7-dimethoxyquinazolin-4-yl)pentyl)sulfamoyl)carbamate Int-5(200 mg, 0.44 mmol) in dioxane (2 ml) was added 4M HCl in dioxane (7 mL)at 0° C. then stirred at room temperature for 16 h. The progress of thereaction was monitored by TLC. After completion of the reaction, organicsolvents completely distilled off under reduced pressure. Crude waspurified through prep HPLC method to afford N-(5-(6,7-dimethoxyquinazolin-4-yl) pentyl) sulfamide (50 mg, 0.141 mmol, 29%yield) as a pale yellow solid.

Analytical Data: 1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 7.43 (s, 1H),7.31 (s, 1H), 6.44 (s, 3H), 3.96 (d, 6H), 3.18 (t, 2H), 2.85 (dd, 2H),1.85-1.73 (m, 2H), 1.56-1.46 (m, 2H), 1.42 (d, 2H)

Compound Number Structure 1HNMR 051

1 H NMR (400 MHz, DMSO): δ 8.93 (s, 1H), 7.43 (s,1H), 7.31 (s, 1H),6.44- 6.41 (m, 3H), 3.96 (s, 6H), 3.19 (t, 2H), 2.84-2.82 (m, 2H),1.81-1.74 (m, 2H), 1.48-1.42 (m, 2H), 1.37-1.36 (m, 4H). MS 369.3

In Vitro Biology Example 1: ENPP1 Assay (TMP)

Materials:

Assay Buffer: 1 mM CaCl₂, 0.2 mM ZnCl₂, 50 mM Tris, pH 9.0

Substrate: 1.5 mM Thymidine 5′-monophosphate disodium salt hydrate(Sigma: T4510)—Assay Cone.: 150 μM

Enzyme: 1 ng/μL Recombinant Human ENPP-1 Protein (purifiedin-house)—Assay Cone.: 5 ng/well

DMSO

96-well clear assay plates

Protocol:

A ten point serial dilution of drugs was prepared in 10× in assay bufferwith the final assay concentrations starting at 10 μM, 3 μM, 1 μM, 0.3μM . . . 0 μM. A dilution of DMSO was included as a control. The assayplate was set up as follows with each well in duplicate: 75 μL assaybuffer+10 μL ENPP1 inhibitor or DMSO Dilutions+10 μL Substrate+5 μLEnzyme (5 ng). Both the enzyme and substrate were added to oppositesides of the well to ensure that there was no interaction until allwells had both components. The plate was then centrifuged gently for 10seconds, followed by an incubation at 37° C. for 45 minutes. Thereaction was quantified by measuring absorbance at 405 nm using theEnvision Plate Reader. Data was analyzed using GraphPad Prism 8.0.

The results are shown below in Table 1:

TABLE 1 Compound IC50 Number (nM) 053 3.60 056 6.87 057 46.57 005 36.45006 36.72 007 4.37 008 8.11 013 17.05 015 32.38 018 4.23 020 99.71 022116.20 026 117.8 027 20.96 028 35.74 029 1.21 032 4.80 033 80.66 03481.14 036 18.12 038 0.94 038-E1 4.95 038-E2 18.0 039 0.87 039-E1 0.50039-E2 0.22 040-E1 67.38 040-E2 41.71 041 10.23 042 40.52 043 3.92 0469.8 047 67.11 048 60.36 049 1.79 050 20.12 063 68.1 054 23.81 058 3.06060 4.34 061 28.88 015-MES 6.38 015-HCl 5.97 065 7.74 064 71.99

Example 2: ENPP1 Thermal Shift Assay

Materials:

Recombinant Human ENPP-1 Protein (Purified In-House)

Assay Buffer (1 mM CaCl₂, 0.2 mM ZnCl₂, 50 mM Tris, pH 9.0)

5000×SYPRO Orange (ThermoFisher cat #S6651)

384-well PCR Plates

Protocol:

Each drug was prepared as a 1 Ox solution in the assay buffer and SYPROOrange was diluted to 10× concentration in water. Wells were set up induplicate in a 384-well PCR plate as follows: 14 μL assay buffer, 2 μLENPP1 Inhibitor or DMSO, 2 μL (0.5 μg) ENPP1 protein. Each well wasmixed and incubated on ice for 5 minutes. Post incubation, 2 μL of SYPROOrange was mixed into each well and followed by a gentle centrifugation.The protein melt reaction was run using ViiA7 software with temperaturesbeginning at 25° C. and increasing by 0.05° C./s to the maximumtemperature of 99° C.

Thermal Shift Compd# @10 uM(dTm(o C.){circumflex over ( )} 047 $$ 048 $$049 $$$ 050 $$ 051 NC 052 NC 053 $$$ 054 $$ 055 $$ 056 $$ 057 $$ 058 $$$059 NC 060 $$$ 061 $$ 062 $$ 015-HCl $$$ 005 $$ 063 $$ 065 $$$ 064 $${circumflex over ( )}$$ <3o C.; $$$ >3o C.; NC, Not Calculated

Example 3: ENPP2 Assay

Materials:

Assay Buffer: 50 mM Tris, 10 mM CaCl₂, 5 mM MgCl₂, 0.02% Brij-35 (v/v),pH 8.5

Substrate: 20 mM Bis(p-Nitrophenyl) Phosphate Sodium Salt (BPNPP)(Sigma, Catalog #N3002)

Enzyme: 0.01 ng/μL Recombinant Human ENPP-2/Autotaxin (rhENPP-2) (R&DCatalog #5255-EN)

DMSO

PF8380 (Selleck S8218)

96-well clear assay plates

Protocol:

An eight point serial dilution of drugs was prepared in 10× in assaybuffer with the final assay concentrations starting at 10 μM, 3 μM, 1μM, 0.3 μM . . . 0 μM. A dilution of DMSO was included as a control. Theassay plate was set up as follows with each well in duplicate: 81 μLassay buffer+10 μL ENPP1 inhibitor or DMSO+5 μL Substrate+5 μL Enzyme(0.05 ng). Both the enzyme and substrate were added to opposite sides ofthe well to ensure that there was no interaction until all wells hadboth components. The plate was then centrifuged gently for 10 seconds,followed by an incubation at 37° C. for 10 minutes. The reaction wasquantified by measuring absorbance at 400 nm using the Envision. PF8380was used as a positive control for the assay. Data was analyzed usingGraphPad Prism 8.0.

ENPP2 Compd# Activity{circumflex over ( )} 047 ** 048 ** 049 ** 050 **051 NC 052 NC 053 NC 054 NC 055 NC 056 ** 057 NC 058 NC 059 NC 060 **061 NC 062 ** 015-HCl ** 005 NC 063 ** 065 ** 064 NC {circumflex over( )}** >1 μM; *** <1 μM; NC, Not Calculated

Example 4: Cell-Based ENPP Selectivity Assay (TMP)

Materials:

HEK293T cells

Media: 89% DMEM, 10% FBS, 1% Penicillin/Streptomycin

Transfection Reagent: Polyethylenimine Branched, 1 mg/mL (Sigma: 408719)

Transfection Media: Opti-MEM Reduced Serum Medium (ThermoFisher:31985088)

Plasmid Constructs:

pCMV6 empty construct (Origene: PS100001)

hENPP1 (Origene: RC209222)

hENPP3 (Genscript: OHu19400D)

mENPP1 (Origene: MR227498)

Assay Buffer: 1 mM CaCl2, 0.2 mM ZnCl2, 50 mM Tris, pH 9.0

Substrate: 8 mM Thymidine 5′-monophosphate disodium salt hydrate (SigmaCat #T7004-1G)

6-well tissue culture treated plates

96-well clear assay plates

Protocol:

HEK293T cells were seeded in a 6 well tissue culture treated plate at5×10⁵ cells per well. Transfection mixtures containing 7 μL oftransfection reagent, 2 μg of plasmid construct, and 200 μL oftransfection media were incubated for 20 minutes at room temperature.Transfection mixtures were added dropwise to each well and incubated at37° C./5% CO₂ for 48 hours. Transfected cells were collected bytrypsinization, lysed, and protein concentrations were determined. Drugswere prepared at 10× in assay buffer and tested at a final assayconcentration of 1 μM. Lysate (3 μg) was incubated with 10 μL ENPP1inhibitor and 81 μL assay buffer for 2 hours at 4° C. prior to theaddition of 5 μL of substrate. The final reaction was incubated at 37°C. for 45 minutes and quantified by measuring absorbance at 405 nm usingthe Envision plate reader. The data were normalized to empty constructcontrols.

The results are shown in FIG. 1 .

Example 5: Solubility and Stability Assay

Materials:

PBS pH 7.4 (Catalog #10010-031; from Thermo Fisher Scientific),

FaSSIF (pH 6.5), FeSSIF (pH 5.0) and FaSSGF (pH 1.6) aqueous buffers(Catalog #FFF01, #FASBUF01, #FESBUF01, #FASGBUF01 from biorelevant.com)

Protocol:

1 mg of powder for each compound was combined with 1 mL of buffer tomake a 1 mg/mL mixture. These samples were stirred in magnetic stirrerwith beads for overnight at room temperature. The samples were thenpassed through a 0.45μ PTFE syringe filter. The filtrates were dilutedwith the corresponding buffer before analysis. All samples were assayedby UV-VIS spectrophotometry (Thermo scientific, Nanodrop 8000) againststandards. Samples were kept at RT (room temperature) and atcorresponding time points aliquots were subjected to UV-VISspectrophotometry analysis to measure stability.

Example 6: Immune Infiltration Assay

Materials:

HP AC (ATCC Catalog #: CRL-2119)

Matrigel Matrix Growth Factor Reduced (Corning Catalog #: 354230)

96-well Spheroid Microplates: ULA, Round Bottom, black walled plates(Corning Catalog #: 10185-094)

Corning HTS Transwell 96 well permeable supports, 5 μm (Corning Catalog#: 3387)

DMEM, high glucose, HEPES, no phenol red (ThermoFisher ScientificCatalog #: 21063045)

Human PBMC Peripheral Blood Mono, cryo amp (Lonza Catalog #: CC-2702)

Molecular Probes CellTracker CM Dil Dye (ThermoFisher Scientific Catalog#: C7000)

10× Drug

Protocol:

HP AC cells were cultured according to the ATCC guidelines. On theinitial day of the experiment, 5,000 cells were plated in the 96-wellspheroid microplates in 50 μL of media containing 1.5% matrigel. Thecells were centrifuged at 1800 RPM for 2 minutes and then incubated on aplate shaker at low speed at 37° C./5% CO₂ for 72 hours to allowformation of a single spheroid per well. After incubation, 150 μL ofmedia containing either vehicle (DMSO) or drug was added to eachcorresponding well and incubated for 1 hour at 37° C./5% CO₂. Duringincubation, human PBMCS were counted and fluorescently stained withMolecular Probes CellTracker CM Dil Dye using the manufacturer'sprotocol. After the 1-hour incubation with drug, a transwell plate wasgently placed into the spheroid plate. The PBMCs were then washed andadded to each corresponding well at 400,000 cells/100 μL of media. Theexperiment was incubated at 37° C./5% CO₂ for 48 hours to allow forinfiltration of the immune cells into the spheroids. Followingincubation, the transwell was removed and RFP fluorescence and brightfield Z-stack images were taken for each spheroid using the BiotekCytation5. The images were compressed and the total RFP expression wasassessed. The data was analyzed using GraphPad Prism 8.0.

Prophetic Pharmaceutical Composition Examples

“Active ingredient” as used throughout these examples relates to one ormore of the compounds of the invention, or a pharmaceutically acceptablesalt, solvate, polymorph, hydrate and the stereochemically isomeric formthereof. The following examples of the formulation of the compounds ofthe present invention in tablets, suspension, injectables and ointmentsare prophetic.

Typical examples of recipes for the formulation of the invention are asgiven below. Various other dosage forms can be applied herein such as afilled gelatin capsule, liquid emulsion/suspension, ointments,suppositories or chewable tablet form employing the disclosed compoundsin desired dosage amounts in accordance with the present invention.Various conventional techniques for preparing suitable dosage forms canbe used to prepare the prophetic pharmaceutical compositions, such asthose disclosed herein and in standard reference texts, for example theBritish and US Pharmacopoeias, Remington's Pharmaceutical Sciences (MackPublishing Co.) and Martindale The Extra Pharmacopoeia (London ThePharmaceutical Press). The disclosure of this reference is herebyincorporated herein by reference.

a. Pharmaceutical Composition for Oral Administration

A tablet can be prepared as follows:

Component Amount Active ingredient 10 to 500 mg    Lactose 100 mgCrystalline cellulose  60 mg Magnesium stearate 5  Starch Amountnecessary to yield (e.g. potato starch) total weight indicated belowTotal (per capsule) 1000 mg 

Alternatively, about 100 mg of a disclosed compound, 50 mg of lactose(monohydrate), 50 mg of maize starch (native), 10 mg ofpolyvinylpyrrolidone (PVP 25) (e.g. from BASF, Ludwigshafen, Germany)and 2 mg of magnesium stearate are used per tablet. The mixture ofactive component, lactose and starch is granulated with a 5% solution(m/m) of the PVP in water. After drying, the granules are mixed withmagnesium stearate for 5 min. This mixture is moulded using a customarytablet press (e.g. tablet format: diameter 8 mm, curvature radius 12mm). The moulding force applied is typically about 15 kN.

Alternatively, a disclosed compound can be administered in a suspensionformulated for oral use. For example, about 100-5000 mg of the desireddisclosed compound, 1000 mg of ethanol (96%), 400 mg of xanthan gum, and99 g of water are combined with stirring. A single dose of about 10-500mg of the desired disclosed compound according can be provided by 10 mlof oral suspension.

In these Examples, active ingredient can be replaced with the sameamount of any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds. Insome circumstances it may be desirable to use a capsule, e.g. a filledgelatin capsule, instead of a tablet form. The choice of tablet orcapsule will depend, in part, upon physicochemical characteristics ofthe particular disclosed compound used.

Examples of alternative useful carriers for making oral preparations arelactose, sucrose, starch, talc, magnesium stearate, crystallinecellulose, methyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, carboxymethyl cellulose, glycerin, sodiumalginate, gum arabic, etc. These alternative carriers can be substitutedfor those given above as required for desired dissolution, absorption,and manufacturing characteristics.

The amount of a disclosed compound per tablet for use in apharmaceutical composition for human use is determined from bothtoxicological and pharmacokinetic data obtained in suitable animalmodels, e.g. rat and at least one non-rodent species, and adjusted basedupon human clinical trial data. For example, it could be appropriatethat a disclosed compound is present at a level of about 10 to 1000 mgper tablet dosage unit.

b. Pharmaceutical Composition for Injectable Use

A parenteral composition can be prepared as follows:

Component Amount Active ingredient 10 to 500 mg     Sodium carbonate 560mg* Sodium hydroxide  80 mg* Distilled, sterile water Quantitysufficient to prepare total volumen indicated below. Total (per capsule)     10 ml per ampule *Amount adjusted as required to maintainphysiological pH in the context of the amount of active ingredient, andform of active ingredient, e.g. a particular salt form of the activeingredient.

Alternatively, a pharmaceutical composition for intravenous injectioncan be used, with composition comprising about 100-5000 mg of adisclosed compound, 15 g polyethyleneglycol 400 and 250 g water insaline with optionally up to about 15% Cremophor EL, and optionally upto 15% ethyl alcohol, and optionally up to 2 equivalents of apharmaceutically suitable acid such as citric acid or hydrochloric acidare used. The preparation of such an injectable composition can beaccomplished as follows: The disclosed compound and thepolyethyleneglycol 400 are dissolved in the water with stirring. Thesolution is sterile filtered (pore size 0.22 μm) and filled into heatsterilized infusion bottles under aseptic conditions. The infusionbottles are sealed with rubber seals.

In a further example, a pharmaceutical composition for intravenousinjection can be used, with composition comprising about 10-500 mg of adisclosed compound, standard saline solution, optionally with up to 15%by weight of Cremophor EL, and optionally up to 15% by weight of ethylalcohol, and optionally up to 2 equivalents of a pharmaceuticallysuitable acid such as citric acid or hydrochloric acid. Preparation canbe accomplished as follows: a desired disclosed compound is dissolved inthe saline solution with stirring. Optionally Cremophor EL, ethylalcohol or acid are added. The solution is sterile filtered (pore size0.22 μm) and filled into heat sterilized infusion bottles under asepticconditions. The infusion bottles are sealed with rubber seals.

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

The amount of a disclosed compound per ampule for use in apharmaceutical composition for human use is determined from bothtoxicological and pharmacokinetic data obtained in suitable animalmodels, e.g. rat and at least one non-rodent species, and adjusted basedupon human clinical trial data. For example, it could be appropriatethat a disclosed compound is present at a level of about 10 to 1000 mgper tablet dosage unit.

Carriers suitable for parenteral preparations are, for example, water,physiological saline solution, etc. which can be used withtris(hydroxymethyl)aminomethane, sodium carbonate, sodium hydroxide orthe like serving as a solubilizer or pH adjusting agent. The parenteralpreparations contain preferably 50 to 1000 mg of a disclosed compoundper dosage unit.

Example 7 In Vivo Methods

Study I: Determination of the Bioavailability of 015-HCl FollowingIntravenous and Oral Administration in Male Sprague-Dawley Rats

The compound 015-HCl was dosed by intravenous (IV) and oral (PO) routesof administration at 2 and 10 mg/kg, respectively. Blood samples werecollected up to 24 hours post-dose, and blood concentrations of 015-HClwere determined by LC-MS/MS. Pharmacokinetic parameters were determinedusing Phoenix WinNonlin (v8.0) software.

Study II: Anti-Tumor Efficacy of Compound 015-HCl in PAN02 (MousePancreatic Ductal Adenocarcinoma Model) Syngeneic Model of C57BL/6 Mice

Experimental Design

Animals: Female C57BL/6 (4-6 Week's Age from Charles RiverLaboratories).

The PAN02 cells were propagated in DMEM cell culture medium containing10% Fetal Bovine Serum. Cells were harvested in logarithmic growth phaseand implanted subcutaneously (1×10⁶) in the lower abdomen of mice. Tumorgrowth was monitored daily and after the tumors had reached 80 to 100mm³, mice were randomized into groups consisting of 10 animals per groupand treated as shown in Table 2. Animals were euthanized when tumorsreached around 2000 mm³ or treatment regime completed or 20% of bodyweight loss, or developed ulceration and necrosis. Upon termination,tumor samples and blood was collected and analyzed for biomarkers.

TABLE 2 Study design, number of groups, route and doses No. of DoseGroups animals Dose Route regimen Vehicle 10 — P.O BID G1 Compound 10 50 P.O BID 015-HCl mg/kg G2 Compound 10 150 P.O BID 015-HCl mg/kg G3Compound 10 300 P.O. BID 015-HCl mg/kg G4 Compound 10 150 P.O. QD015-HCl mg/kg G5Study III: Anti-Tumor Efficacy of Compound 015-HCl in MC38 (ColonAdenocarcinoma Mouse Model) Syngeneic Model of C57BL/6 MiceExperimental Design

Animals: Female C57BL/6 (4-6 week's age from Charles RiverLaboratories). The MC38 cells were propagated in RPMI cell culturemedium containing 10% Fetal Bovine Serum. Cells were harvested inlogarithmic growth phase and implanted subcutaneously (2×10⁵) in flankof mice. Tumor growth was monitored daily and after the tumors hadreached about 100 mm³, mice were randomized into groups consisting of 10animals per group. On Day 17, mice were treated with 015-HCl compound orvehicle as shown in Table 3. On day 18, groups 2, 5, and 6 were given asingle 10 Gy exposure of focal radiation to the tumor site. Animals wereeuthanized when tumors reached around 2000 mm³ or treatment regimecompleted or 20% of body weight loss, or developed ulceration andnecrosis. Upon termination, tumor samples and blood were collected andanalyzed for biomarkers.

TABLE 3 Study design, number of groups, route and doses No. of DoseGroups animals Dose Route regimen Vehicle 10 — I.P BID G1 Radiation 1010 Gy Rad — BID G2 Compound 10 50 mg/kg I.P. BID G3 Compound + 10 50mg/kg + I.P. BID Radiation 10 Gy Rad G5

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

What is claimed is:
 1. A compound of Formula II:

wherein X is N or CR₁₁; Z is C or N; W is selected from the groupconsisting of an C₁-C₅ alkyl, —C(═O)—(CH₂)_(n)—, —(C₁-C₅ alkyl)-N—; NH,and a direct bond as follows:

each R₁, R₂ and R₃ are independently selected from the group consistingof hydrogen, halogen, CN, OR^(a), —C(═O)NR^(b)R^(c), —NR^(b)R^(c),—C(═O)R^(d), aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; eachR^(a) is independently selected from the group consisting of hydrogen,lower alkyl, and —(CH₂)_(n)—C(═O)NR^(b)R^(c), aralkyl, aryl, heteroaryl,heterocycloalkyl, cycloalkyl; wherein n is an integer between 1 and 3;each R^(b) and R^(c) is independently selected from the group consistingof hydrogen, a lower alkyl, and lower aryl, heterocycloalkyl, orcycloalkyl; each R^(d) is independently selected from the groupconsisting of —OR^(e) and lower alkyl; each R^(e) is independentlyselected from the group consisting of hydrogen, a lower alkyl, and alower aryl; R₁₁ is independently selected from the group consisting ofhydrogen, halogen, COOEt, COOH, and CN; R₇, R₈ and R₉ are independentlyselected from the group consisting of H, halogen and lower alkyl; and R₈and R₉ can also form a bridge across the 7-membered ring with 1 or 2atoms, as follows:

R₁₀ is independently selected from the group consisting of hydrogen andCF₃; or an isomer, hydrate, solvate, polymorph, tautomer or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,wherein Z is N.
 3. The compound of claim 1, wherein W is selected fromthe group consisting of -4,5-imidazole, 2-Oxazole, 3-pyrrole; pyrazole,and thiazole.
 4. The compound of claim 1, wherein R₁, R₂ and R₃ areselected form CH₃O or H.
 5. The compound of claim 1, wherein X is N. 6.The compound of claim 1, wherein X is C—CN.
 7. The compound of claim 1,wherein R₇, R₈ and R₉ are independently selected from the groupconsisting of H and halogen.
 8. The compound of claim 1, wherein R₇ is ahalogen.
 9. The compound of claim 8, wherein the halogen is F.
 10. Thecompound of claim 1, wherein R₈ and R₉ are both halogen.
 11. Thecompound of claim 10, wherein the halogen is F.
 12. The compound ofclaim 1, wherein X is N; Z is N; W is selected from the group consistingof C₁-C₅ alkyl, —C(═O)—(CH₂)—, —(C₁-C₅ alkyl)-N; and a direct bond; andR₁, R₂ and R₃ are selected form CH₃O or H.
 13. A compound is selectedfrom the group consisting of


14. The compound of claim 1 having the following structure:

or a pharmaceutically acceptable salt thereof.
 15. The compound of claim1 having the following structure:

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim1 having the following structure:

or a pharmaceutically acceptable salt thereof.
 17. The compound of claim1 having the following structure:

or a pharmaceutically acceptable salt thereof.
 18. The compound of claim1 having the following structure:

or a pharmaceutically acceptable salt thereof.
 19. The compound of claim1 having the following structure:

or a pharmaceutically acceptable salt thereof.
 20. The compound of claim1 having the following structure:

or a pharmaceutically acceptable salt thereof.
 21. The compound of claim1 having the following structure:

or a pharmaceutically acceptable salt thereof.
 22. The compound of claim1 having the following structure:

or a pharmaceutically acceptable salt thereof.
 23. The compound of claim1 having the following structure:

or a pharmaceutically acceptable salt thereof.
 24. The compound of claim1 having the following structure:

or a pharmaceutically acceptable salt thereof.
 25. The compound of claim1 having the following structure:

or a pharmaceutically acceptable salt thereof.
 26. The compound of claim1 having the following structure:

or a pharmaceutically acceptable salt thereof.
 27. The compound of claim1 having the following structure:

or a pharmaceutically acceptable salt thereof.
 28. The compound of claim1 having the following structure:

or a pharmaceutically acceptable salt thereof.
 29. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 and a pharmaceutically acceptable carrier.
 30. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 13 and a pharmaceutically acceptable carrier. 31.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 14 and a pharmaceutically acceptablecarrier.
 32. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 15 and a pharmaceuticallyacceptable carrier.
 33. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 16 and apharmaceutically acceptable carrier.
 34. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound of claim 17and a pharmaceutically acceptable carrier.
 35. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 18 and a pharmaceutically acceptable carrier.
 36. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 19 and a pharmaceutically acceptable carrier. 37.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 20 and a pharmaceutically acceptablecarrier.
 38. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 21 and a pharmaceuticallyacceptable carrier.
 39. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 22 and apharmaceutically acceptable carrier.
 40. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound of claim 23and a pharmaceutically acceptable carrier.
 41. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 24 and a pharmaceutically acceptable carrier.
 42. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 25 and a pharmaceutically acceptable carrier. 43.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 26 and a pharmaceutically acceptablecarrier.
 44. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 27 and a pharmaceuticallyacceptable carrier.
 45. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 28 and apharmaceutically acceptable carrier.